FERM domain C-lobe of FERM domain-containing protein 3 and 5 (FRMD3 and 5); FRMD3 (also called Band 4.1-like protein 4O/4.1O though it is not a true member of that family) is a novel putative tumor suppressor gene that is implicated in the origin and progression of lung cancer. In humans there are 5 isoforms that are produced by alternative splicing. Less is known about FRMD5, though there are 2 isoforms of the human protein are produced by alternative splicing. Both FRMD3 and FRMD5 contain a N-terminal FERM domain, followed by a FERM adjacent (FA) domain, and 4.1 protein C-terminal domain (CTD). The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349 191 SELNFLRKAQTLETYGVDPHPCKDVSGNAAFLAFTPFGFVVLQGNKRVHFIKWNEVTKLKFEGKTFYLYVSQKEEKKIIL 270
Cdd:cd13192     1 AEDNFLRKAATLETYGVDPHPVKDHRGNQLYLGFTHTGIVTFQGGKRVHHFRWNDITKFNYEGKMFILHVMQKEEKKHTL 80

                          90       100
                  ....*....|....*....|....*
gi 1334928349 271 TYFAPTPEACKHLWKCGIENQAFYK 295
Cdd:cd13192    81 GFKCPTPAACKHLWKCAVEQQAFYT 105

FERM adjacent (FA); This region is found adjacent to Band 4.1 / FERM domains (pfam00373) in a subset of FERM containing protein. The region has been hypothesized to play a role in regulatory adaptation, based on similarity to other protein kinase substrates.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1334928349 309 NLFFKGSRFRYSGRVAKEVMESSAKIKREPPEIHRagmVPSRSCPS 354
Cdd:pfam08736   1 KFFSLGSKFRYSGRTQKQTVEDSSEILRPQPEFER---SPSKRYPS 43

FERM domain C-lobe of FERM domain-containing protein 3 and 5 (FRMD3 and 5); FRMD3 (also called Band 4.1-like protein 4O/4.1O though it is not a true member of that family) is a novel putative tumor suppressor gene that is implicated in the origin and progression of lung cancer. In humans there are 5 isoforms that are produced by alternative splicing. Less is known about FRMD5, though there are 2 isoforms of the human protein are produced by alternative splicing. Both FRMD3 and FRMD5 contain a N-terminal FERM domain, followed by a FERM adjacent (FA) domain, and 4.1 protein C-terminal domain (CTD). The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349 191 SELNFLRKAQTLETYGVDPHPCKDVSGNAAFLAFTPFGFVVLQGNKRVHFIKWNEVTKLKFEGKTFYLYVSQKEEKKIIL 270
Cdd:cd13192     1 AEDNFLRKAATLETYGVDPHPVKDHRGNQLYLGFTHTGIVTFQGGKRVHHFRWNDITKFNYEGKMFILHVMQKEEKKHTL 80

                          90       100
                  ....*....|....*....|....*
gi 1334928349 271 TYFAPTPEACKHLWKCGIENQAFYK 295
Cdd:cd13192    81 GFKCPTPAACKHLWKCAVEQQAFYT 105

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM domain-containing protein 3 (FRMD3) and similar proteins; FRMD3, also termed band 4.1-like protein 4O, or ovary type protein 4.1 (4.1O), belongs to the 4.1 protein superfamily, which share the highly conserved membrane-association FERM domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N). FRMD3 is involved in maintaining cell shape and integrity. It also functions as a tumour suppressor in non-small cell lung carcinoma (NSCLC). Some single nucleotide polymorphisms (SNPs) located in FRMD3 have been associated with diabetic kidney disease (DKD) in different ethnicities.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349  17 YSCTVRLLDDSEYTCTIQR-DAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQLRSQPPFTMCFRVK 95
Cdd:cd17102     1 YKCTIRLLDDSEVICCEFKkDTKGQFLLDYVCNYLNLLEKDYFGLRYVDTEKQRHWLDPNKSIYKQLKGVPPYVLCFRVK 80

                  ..
gi 1334928349  96 FY 97
Cdd:cd17102    81 FY 82

FERM C-terminal PH-like domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349 214 DVSGNAAFLAFTPFGFVVLQGNKRV-HFIKWNEVTKLKFEGKTFYLYVSQKEeKKIILTYFAPTPEACKHLWKCGIENQA 292
Cdd:pfam09380   1 DKEGTDLWLGVSAKGILVYEDNNKIlNLFPWREIRKISFKRKKFLIKLRDKS-SEETLGFYTESSRACKYLWKLCVEQHT 79

                  ....*.
gi 1334928349 293 FYKLEK 298
Cdd:pfam09380  80 FFRLRR 85

FERM domain C-lobe of FERM domain-containing protein 3 and 5 (FRMD3 and 5); FRMD3 (also called Band 4.1-like protein 4O/4.1O though it is not a true member of that family) is a novel putative tumor suppressor gene that is implicated in the origin and progression of lung cancer. In humans there are 5 isoforms that are produced by alternative splicing. Less is known about FRMD5, though there are 2 isoforms of the human protein are produced by alternative splicing. Both FRMD3 and FRMD5 contain a N-terminal FERM domain, followed by a FERM adjacent (FA) domain, and 4.1 protein C-terminal domain (CTD). The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349 191 SELNFLRKAQTLETYGVDPHPCKDVSGNAAFLAFTPFGFVVLQGNKRVHFIKWNEVTKLKFEGKTFYLYVSQKEEKKIIL 270
Cdd:cd13192     1 AEDNFLRKAATLETYGVDPHPVKDHRGNQLYLGFTHTGIVTFQGGKRVHHFRWNDITKFNYEGKMFILHVMQKEEKKHTL 80

                          90       100
                  ....*....|....*....|....*
gi 1334928349 271 TYFAPTPEACKHLWKCGIENQAFYK 295
Cdd:cd13192    81 GFKCPTPAACKHLWKCAVEQQAFYT 105

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM domain-containing protein 3 (FRMD3) and similar proteins; FRMD3, also termed band 4.1-like protein 4O, or ovary type protein 4.1 (4.1O), belongs to the 4.1 protein superfamily, which share the highly conserved membrane-association FERM domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N). FRMD3 is involved in maintaining cell shape and integrity. It also functions as a tumour suppressor in non-small cell lung carcinoma (NSCLC). Some single nucleotide polymorphisms (SNPs) located in FRMD3 have been associated with diabetic kidney disease (DKD) in different ethnicities.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349  17 YSCTVRLLDDSEYTCTIQR-DAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQLRSQPPFTMCFRVK 95
Cdd:cd17102     1 YKCTIRLLDDSEVICCEFKkDTKGQFLLDYVCNYLNLLEKDYFGLRYVDTEKQRHWLDPNKSIYKQLKGVPPYVLCFRVK 80

                  ..
gi 1334928349  96 FY 97
Cdd:cd17102    81 FY 82

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain and F1 sub-domain, found in FERM (Four.1/Ezrin/Radixin/Moesin) family proteins; FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain is present at the N-terminus of a large and diverse group of proteins that mediate linkage of the cytoskeleton to the plasma membrane. FERM-containing proteins are ubiquitous components of the cytocortex and are involved in cell transport, cell structure and signaling functions. The FERM domain is made up of three sub-domains, F1, F2, and F3. The family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N), which is structurally similar to ubiquitin.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1334928349  18 SCTVRLLDDSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQLRSQPPFTMCFRVKF 96
Cdd:cd01765     2 SCRVRLLDGTELTLEVSKKATGQELFDKVCEKLNLLEKDYFGLFYEDNDGQKHWLDLDKKISKQLKRSGPYQFYFRVKF 80

FERM domain B-lobe; The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases, the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349 109 TRYLVFLQIKRDLYHGRLLCKTSDAALLAAYILQAEIGDYDPGKHPEGYSSKFQFFPKH------SEKLEKKIAEIHKtE 182
Cdd:cd14473     1 TRYLLYLQVKRDILEGRLPCSEETAALLAALALQAEYGDYDPSEHKPKYLSLKRFLPKQllkqrkPEEWEKRIVELHK-K 79

                          90       100
                  ....*....|....*....|
gi 1334928349 183 LSGQTPATSELNFLRKAQTL 202
Cdd:cd14473    80 LRGLSPAEAKLKYLKIARKL 99

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in erythrocyte membrane protein band 4.1-like protein 3 (EPB41L3) and similar proteins; EPB41L3, also termed 4.1B, or differentially expressed in adenocarcinoma of the lung protein 1 (DAL-1), belongs to the skeletal protein 4.1 family that is involved in cellular processes such as cell adhesion, migration and signaling. EPB41L3 is a tumor suppressor that has been implicated in a variety of meningiomas and carcinomas. EPB41L3 contains a FERM domain, a spectrin and actin binding (SAB) domain, and a C-terminal domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349  19 CTVRLLDDSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQLRSQpPFTMCFRVKFYP 98
Cdd:cd17203     4 CKVTLLDGSEYTCEVEKRSKGQVLFDKVCEHLNLLEKDYFGLTYRDSENQKNWLDPAKEIKKQIRSG-AWQFSFNVKFYP 82

                  ..
gi 1334928349  99 AD 100
Cdd:cd17203    83 PD 84

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in erythrocyte membrane protein band 4.1-like protein 2 (EPB41L2) and similar proteins; EPB41L2, also termed generally expressed protein 4.1 (4.1G), belongs to the skeletal protein 4.1 family that is involved in cellular processes such as cell adhesion, migration and signaling. EPB41L2 contains a FERM domain, a spectrin and actin binding (SAB) domain, and a C-terminal domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349  19 CTVRLLDDSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQLRSQpPFTMCFRVKFYP 98
Cdd:cd17202     4 CKVTLLDGTEYSCDLEKRAKGQVLFDKVCEHLNLLEKDYFGLLYQVSANQKNWLDSTKEIKRQIRRL-PWLFTFNVKFYP 82

                  ..
gi 1334928349  99 AD 100
Cdd:cd17202    83 PD 84

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in erythrocyte membrane protein band 4.1 (EPB41) and similar proteins; EPB41, also termed protein 4.1 (P4.1), or 4.1R, or Band 4.1, or EPB4.1, belongs to the skeletal protein 4.1 family that is involved in cellular processes such as cell adhesion, migration and signaling. EPB41 is a widely expressed cytoskeletal phosphoprotein that stabilizes the spectrin-actin cytoskeleton and anchors the cytoskeleton to the cell membrane. EPB41 contains a FERM domain, a spectrin and actin binding (SAB) domain, and a C-terminal domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349  19 CTVRLLDDSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQLRSqPPFTMCFRVKFYP 98
Cdd:cd17105     3 CKVSLLDDTVYECEVEKHAKGQDLFKKVCEHLNLLEEDYFGLAIWDSPTSKTWLDPAKEIKKQVHG-GPWEFTFNVKFYP 81

                  ..
gi 1334928349  99 AD 100
Cdd:cd17105    82 PD 83

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in erythrocyte membrane protein band 4.1-like 5 (EPB41L5); EPB41L5 is a mesenchymal-specific protein that is an integral component of the ARF6-based pathway. It is normally induced during epithelial-mesenchymal transition (EMT) by an EMT-related transcriptional factor, ZEB1, which drives ARF6-based invasion, metastasis and drug resistance. EPB41L5 also binds to paxillin to enhance integrin/paxillin association, and thus promotes focal adhesion dynamics. Moreover, EPB41L5 acts as a substrate for the E3 ubiquitin ligase Mind bomb 1 (Mib1), which is essential for activation of Notch signaling. EPB41L5 is a member of the band 4.1/Nbl4 (novel band 4.1-like protein 4) group of the FERM protein superfamily. It contains a FERM domain that is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349  18 SCTVRLLDDSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQLRSQPPFTMCFRVKFY 97
Cdd:cd17205     4 TCRVSLLDGTDVSVDLPKKAKGQELFEQIMYHLDLIEKDYFGLRFMDSAQVAHWLDVTKSIKKQVKIGPPYCLHLRVKFY 83

                  ...
gi 1334928349  98 PAD 100
Cdd:cd17205    84 SSE 86

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in erythrocyte band 4.1-like protein 4B (EPB41L4B); EPB41L4B, also termed FERM-containing protein CG1, or expressed in high metastatic cells (Ehm2), or Lulu2, is a member of the band 4.1/Nbl4 (novel band 4.1-like protein 4) group of the FERM protein superfamily. It contains a FERM domain that is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N). EPB41L4B is a positive regulator of keratinocyte adhesion and motility, suggesting a role in wound healing. It also promotes cancer metastasis in melanoma, prostate cancer and breast cancer.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349  18 SCTVRLLDDSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQLRSQPPFTMCFRVKFY 97
Cdd:cd17204     2 TCRVLLLDGTDVSVELPKHAKGQDLFDQIVYHLDLVETDYFGLQFMDAAQVAHWLDHTKPIKKQIKIGPPYTLHFRIKYY 81

                  ...
gi 1334928349  98 PAD 100
Cdd:cd17204    82 SSE 84

FERM domain C-lobe of Novel band 4.1-like protein 4 and 5 (NBL4 and 5); NBL4 (also called Erythrocyte protein band 4.1-like 4; Epb4 1l4) plays a role the beta-catenin/Tcf signaling pathway and is thought to be involved in establishing the cell polarity or proliferation. NBL4 may be also involved in adhesion, in cell motility and/or in cell-to-cell communication. No role for NBL5 has been proposed to date. Both NBL4 and NBL5 contain a N-terminal FERM domain which has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe is a member of the PH superfamily. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349 206 GVDPHPCKDVSGNAAFLAFTPFGFVVLQGNKRVHFIKWNEVTKLKFEGKTFYLYVSQKEEKKIILTYF--APTPEACKHL 283
Cdd:cd13186     1 GVDLHPVKGEDGNEYFLGLTPTGILVFENKTKIGLFFWPRITKLDFKGKKLKLVVKEKDDQEQEHTFVfrLPNKKACKHL 80

                          90
                  ....*....|..
gi 1334928349 284 WKCGIENQAFYK 295
Cdd:cd13186    81 WKCAVEHHAFFR 92

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM, ARH/RhoGEF and pleckstrin domain-containing protein 1 (FARP1); FARP1, also termed chondrocyte-derived ezrin-like protein (CDEP), or pleckstrin homology (PH) domain-containing family C member 2 (PLEKHC2), is a neuronal activator of the RhoA GTPase. It promotes outgrowth of developing motor neuron dendrites. It also regulates excitatory synapse formation and morphology, as well as activates the GTPase Rac1 to promote F-actin assembly. As a novel downstream signaling partner of Rif, FARP1 is involved in the regulation of semaphorin signaling in neurons. FARP1 contains a FERM domain, a Dbl-homology (DH) domain and two pleckstrin homology (PH) domains. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349  17 YSCTVRLLDDSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQLRSQPPFTMCFRVKF 96
Cdd:cd17189     1 VPIKVQMLDDTQEVFEVPQRAPGKVLLDAVCSHLNLVEGDYFGLEFQDHRKVMVWLDLLKPIVKQIRRPKHVVLRFVVKF 80

                  ....
gi 1334928349  97 YPAD 100
Cdd:cd17189    81 FPPD 84

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM, ARH/RhoGEF and pleckstrin domain-containing protein 2 (FARP2) and similar proteins; FARP2, also termed FERM domain including RhoGEF (FIR), or Pleckstrin homology (PH) domain-containing family C member 3, is a Dbl-family guanine nucleotide exchange factor (GEF) that activates Rac1 or Cdc42 in response to upstream signals, suggesting roles in regulating processes such as neuronal axon guidance and bone homeostasis. It is also a key molecule involved in the response of neuronal growth cones to class-3 semaphorins. FARP2 contains a FERM domain, a Dbl-homology (DH) domain and two pleckstrin homology (PH) domains. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349  19 CTVRLLDDSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQLRSqpPFTMCFR--VKF 96
Cdd:cd17190     3 LRVKLLDNTTEPLEIEPKADGQALLSQVFKRLNLVESDYFGLEFQNSQSNWIWLEPMKLIVKQVRR--PKNTKLRlaVKF 80

                  ....*
gi 1334928349  97 YPADP 101
Cdd:cd17190    81 FPPDP 85

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM domain-containing protein 7 (FRMD7); FRMD7 plays an important role in neuronal development and is involved in the regulation of F-actin, neurofilament, and microtubule dynamics. It interacts with the Rho GTPase regulator, RhoGDIalpha, and activates the Rho subfamily member Rac1, which regulates reorganization of actin filaments and controls neuronal outgrowth. Mutations in the FRMD7 gene are responsible for the X-linked idiopathic congenital nystagmus (ICN), a disease which affects ocular motor control. FRMD7 contains a FERM domain, and a pleckstrin homology (PH) domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349  21 VRLLDDSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQLRSQPPFTMCFRVKFYPAD 100
Cdd:cd17188     6 VQFLDDSQKVFVVDQKSTGKDLFNMSCSHLNLVEKEYFGLEFRNHAGNNVWLELLKPITKQIKNPKELIFKFTVKFFPVD 85

                  .
gi 1334928349 101 P 101
Cdd:cd17188    86 P 86

FERM domain C-lobe of Protein tyrosine phosphatase non-receptor proteins 3 and 4 (PTPN4 and PTPN3); PTPN4 (also called PTPMEG, protein tyrosine phosphatase, megakaryocyte) is a cytoplasmic protein-tyrosine phosphatase (PTP) thought to play a role in cerebellar function. PTPMEG-knockout mice have impaired memory formation and cerebellar long-term depression. PTPN3/PTPH1 is a membrane-associated PTP that is implicated in regulating tyrosine phosphorylation of growth factor receptors, p97 VCP (valosin-containing protein, or Cdc48 in Saccharomyces cerevisiae), and HBV (Hepatitis B Virus) gene expression; it is mutated in a subset of colon cancers. PTPMEG and PTPN3/PTPH1 contains a N-terminal FERM domain, a middle PDZ domain, and a C-terminal phosphatase domain. PTP1/Tyrosine-protein phosphatase 1 from nematodes and a FERM_C repeat 1 from Tetraodon nigroviridis are also included in this cd. The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349 204 TYGVDPHPCKDVSGNAAFLAFTPFGFVVLQGNKRVHFIKWNEVTKLKFEGKTFYLYVSQK--EEKKIILTYFAPTPEACK 281
Cdd:cd13189     1 LYGVELHSARDSNNLELQIGVSSAGILVFQNGIRINTFPWSKIVKISFKRKQFFIQLRREpnESRDTILGFNMLSYRACK 80

                          90
                  ....*....|....*
gi 1334928349 282 HLWKCGIENQAFYKL 296
Cdd:cd13189    81 NLWKSCVEHHTFFRL 95

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in tyrosine-protein phosphatase non-receptor type 3 (PTPN3); PTPN3, also termed protein-tyrosine phosphatase H1 (PTP-H1), belongs to the non-transmembrane FERM-containing protein-tyrosine phosphatase (PTP) subfamily characterized by a conserved N-terminal FERM domain, a PDZ domain, and a C-terminal PTP catalytic domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N). PTPN3 associates with the mitogen-activated protein kinase p38gamma (also known as MAPK12) to form a PTPN3-p38gamma complex that promotes Ras-induced oncogenesis. It may also act as a tumor suppressor in lung cancer through its modulation of epidermal growth factor receptor (EGFR) signaling. Moreover, PTPN3 shows sensitizing effect to anti-estrogens. It dephosphorylates the tyrosine kinase EGFR, disrupts its interaction with the nuclear estrogen receptor, and increases breast cancer sensitivity to small molecule tyrosine kinase inhibitors (TKIs). It also cooperates with vitamin D receptor to stimulate breast cancer growth through their mutual stabilization.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349  16 EYSCTVRLLDDSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRH-WLEFTKSVVKQLRSQPPFTMCFRV 94
Cdd:cd17193     1 EVICNVHFLDGSVQSFKVNKQDTGQVLLDMAYNHLGLTEREYFGLQHNEDSVDSPrWLEPSKPIRKQLKGGFPCSLHFRV 80

                  ...
gi 1334928349  95 KFY 97
Cdd:cd17193    81 RFF 83

FERM domain C-lobe of Protein 4.1 family; The protein 4.1 family includes four well-defined members: erythroid protein 4.1 (4.1R), the best known and characterized member, 4.1G (general), 4.1N (neuronal), and 4.1 B (brain). The less well understood 4.1O/FRMD3 is not a true member of this family and is not included in this hierarchy. Besides three highly conserved domains, FERM, SAB (spectrin and actin binding domain) and CTD (C-terminal domain), the proteins from this family contain several unique domains: U1, U2 and U3. FERM domains like other members of the FERM domain superfamily have a cloverleaf architecture with three distinct lobes: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The brain is a particularly rich source of protein 4.1 isoforms. The various 4.1R, 4.1G, 4.1N, and 4.1B mRNAs are all expressed in distinct patterns within the brain. It is likely that 4.1 proteins play important functional roles in the brain including motor coordination and spatial learning, postmitotic differentiation, and synaptic architecture and function. In addition they are found in nonerythroid, nonneuronal cells where they may play a general structural role in nuclear architecture and/or may interact with splicing factors. The FERM C domain is the third structural domain within the FERM domain. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349 205 YGVDPHPCKDVSGNAAFLAFTPFGFVVLQGNKRVHFIKWNEVTKLKFEGKTFYLYV--SQKEEKKIILTYFAPTPEACKH 282
Cdd:cd13184     1 YGVDLHPAKDSEGVDIMLGVCSSGLLVYRDRLRINRFAWPKVLKISYKRNNFYIKIrpGEFEQYETTIGFKLPNHRAAKR 80

                          90
                  ....*....|....
gi 1334928349 283 LWKCGIENQAFYKL 296
Cdd:cd13184    81 LWKVCVEHHTFFRL 94

FERM adjacent (FA); This region is found adjacent to Band 4.1 / FERM domains (pfam00373) in a subset of FERM containing protein. The region has been hypothesized to play a role in regulatory adaptation, based on similarity to other protein kinase substrates.

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gi 1334928349 309 NLFFKGSRFRYSGRVAKEVMESSAKIKREPPEIHRagmVPSRSCPS 354
Cdd:pfam08736   1 KFFSLGSKFRYSGRTQKQTVEDSSEILRPQPEFER---SPSKRYPS 43

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in merlin and similar proteins; Merlin, also termed moesin-ezrin-radixin-like protein, or neurofibromin-2 (NF2), or Schwannomerlin, or Schwannomin, is a member of the ezrin/radixin/moesin (ERM) family of cytoskeletal proteins that plays an essential role in microvilli formation, T-cell activation, and tumor metastasis through providing a regulated linkage between F-actin and membrane-associated proteins. These proteins may also function in signaling cascades that regulate the assembly of actin stress fibers. The ERM proteins consist of an N-terminal FERM domain, a coiled-coil (CC) domain and a C-terminal tail segment (C-tail) containing a well-defined actin-binding motif, merlin however lacks the typical actin-binding motif in the C-tail. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N). Merlin plays vital roles in controlling proper development of organ sizes by specifically binding to a large number of target proteins localized both in cytoplasm and nuclei. Merlin may function as a tumor suppressor that functions upstream of the core Hippo pathway kinases Lats1/2 (Wts in Drosophila) and Mst1/2 (Hpo in Drosophila), as well as the nuclear E3 ubiquitin ligase DDB1-and-Cullin 4-associated Factor 1 (DCAF1)-associated cullin 4-Roc1 ligase, CRL4(DCAF1). Merlin may also has a tumor suppressor function in melanoma cells, the inhibition of the proto-oncogenic Na(+)/H(+) exchanger isoform 1 (NHE1) activity.

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gi 1334928349  18 SCTVRLLD-DSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQ-LRSQPPFTMCFRVK 95
Cdd:cd17186     2 TFTVRIVTmDAEMEFNCEMKWKGKDLFDLVCRTIGLRETWYFGLQYTDSKGTVAWLKMDKKVLDQdVPKEEPVTFHFLAK 81

                  ...
gi 1334928349  96 FYP 98
Cdd:cd17186    82 FYP 84

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in radixin and similar proteins; Radixin is a member of the ezrin/radixin/moesin (ERM) family of cytoskeletal proteins that plays an essential role in microvilli formation, T-cell activation, and tumor metastasis through providing a regulated linkage between F-actin and membrane-associated proteins. These proteins may also function in signaling cascades that regulate the assembly of actin stress fibers. The ERM proteins consist of an N-terminal FERM domain, a coiled-coil (CC) domain and a C-terminal tail segment (C-tail) containing a well-defined actin-binding motif. The C-terminal domain can fold back to bind to the FERM domain forming an autoinhibited conformation. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N). Radixin plays important roles in cell polarity, cell motility, invasion and tumor progression. It mediates the binding of F-actin to the plasma membrane after a conformational activation through Akt2-dependent phosphorylation at Thr564. It is also involved in reversal learning and short-term memory by regulating synaptic GABAA receptor density.

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gi 1334928349  26 DSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQ-LRSQPPFTMCFRVKFYP 98
Cdd:cd17238     9 DAELEFAIQPNTTGKQLFDQVVKTVGLREVWFFGLQYVDSKGYSTWLKLNKKVTQQdVKKENPLQFKFRAKFFP 82

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in Ezrin and similar proteins; Ezrin, also termed cytovillin, or villin-2, or p81, is a member of the ezrin/radixin/moesin (ERM) family of cytoskeletal proteins that plays an essential role in microvilli formation, T-cell activation, and tumor metastasis through providing a regulated linkage between F-actin and membrane-associated proteins. These proteins may also function in signaling cascades that regulate the assembly of actin stress fibers. The ERM proteins consist of an N-terminal FERM domain, a coiled-coil (CC) domain and a C-terminal tail segment (C-tail) containing a well-defined actin-binding motif. The C-terminal domain can fold back to bind to the FERM domain forming an autoinhibited conformation. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N). Ezrin is a tyrosine kinase substrate that functions as a cross-linker between actin cytoskeleton and plasma membrane. It has been implicated in the regulation of the proliferation, apoptosis, adhesion, invasion, metastasis and angiogenesis of cancer cells.

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gi 1334928349  26 DSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQ-LRSQPPFTMCFRVKFYP 98
Cdd:cd17239    11 DAELEFAIQPNTTGKQLFDQVVKTIGLREVWYFGLQYVDNKGFPTWLKLDKKVSAQeVRKENPLQFKFRAKFYP 84

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in moesin and similar proteins; Moesin, also termed membrane-organizing extension spike protein, is a member of the ezrin/radixin/moesin (ERM) family of cytoskeletal proteins that plays an essential role in microvilli formation, T-cell activation, and tumor metastasis through providing a regulated linkage between F-actin and membrane-associated proteins. These proteins may also function in signaling cascades that regulate the assembly of actin stress fibers. The ERM proteins consist of an N-terminal FERM domain, a coiled-coil (CC) domain and a C-terminal tail segment (C-tail) containing a well-defined actin-binding motif. The C-terminal domain can fold back to bind to the FERM domain forming an autoinhibited conformation. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N). Moesin is involved in mitotic spindle function through stabilizing cell shape and microtubules at the cell cortex. It is required for the formation of F-actin networks that mediate endosome biogenesis or maturation and transport through the degradative pathway.

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gi 1334928349  26 DSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQ-LRSQPPFTMCFRVKFYP 98
Cdd:cd17237    10 DAELEFAIQPNTTGKQLFDQVVKTIGLREVWFFGLQYQDTKGFSTWLKLNKKVTAQdVRKESPLLFKFRAKFYP 83

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in tyrosine-protein phosphatase non-receptor type 14 (PTPN14) and similar proteins; PTPN14, also termed protein-tyrosine phosphatase pez, or PTPD2, or PTP36, is a widely expressed non-transmembrane cytosolic protein tyrosine phosphatase (PTP). It belongs to the FERM family of PTPs characterized by a conserved N-terminal FERM domain and a C-terminal PTP catalytic domain with an intervening sequence containing an acidic region and a putative SH3 domain-binding sequence. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N). PTPN14 plays a role in the nucleus during cell proliferation. It forms a complex with Kibra and LATS1 proteins and negatively regulates the key Hippo pathway protein Yes-associated protein (YAP) oncogenic function by controlling its localization. It specifically regulates p130 Crk-associated substrate (p130Cas) phosphorylation at tyrosine residue 128 (Y128) in colorectal cancer (CRC) cells. Moreover, PTPN14 may be a critical enzyme in regulating endothelial cell function. It plays a crucial role in organogenesis by inducing transforming growth factor beta (TGFbeta) and epithelial-mesenchymal transition (EMT). It also acts as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia. It regulates the lymphatic function and choanal development through the interaction with the vascular endothelial growth factor receptor 3 (VEGFR3), a receptor tyrosine kinase essential for lymphangiogenesis. Furthermore, PTPN14 functions as a regulator of cell motility through its action on cell-cell adhesion. Beta-Catenin, a central component of adherens junctions, has been identified as a PTPN14 substrate. PTPN14 works as a novel sperm-motility biomarker and a potential mitochondrial protein.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1334928349  21 VRLLDDSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGIRFVDPDKQRHWLEFTKSVVKQL 82
Cdd:cd17191     8 IRLLDSNVIECTLSVESTGQECLEAVAQRLELRETHYFGLWFLSKSQQARWVELEKPLKKQL 69

FERM domain C-lobe of FERM domain containing 1 and 6 proteins; FRMD6 (also called willin and hEx/human expanded) is localized throughout the cytoplasm or along the plasma membrane. The Drosophilla protein Ex is a regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in organ size control and is tumor suppression by restricting proliferation and promoting apoptosis. Surprisingly, hEx is thought to function independently of the Hippo pathway. Instead it is hypothesized that hEx inhibits progression through the S phase of the cell cycle by upregulating p21(Cip1) and downregulating Cyclin A. It is also implicated in the progression of Alzheimer disease. Not much is known about FRMD1 to date. Both FRMD1 and FRMD6 contains a single FERM domain which has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe is a member of the PH superfamily. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

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                  ....*....|....*....|....*....|....*....|.
gi 1334928349 243 WNEVTKLKFEGKTFYLYVSQKEEKkiiLTYFAPTPEACKHL 283
Cdd:cd13185    48 WSNIGKLSFDRKKFEIRPEGSLRK---LTYYTSSDEKSKYL 85

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM and PDZ domain-containing protein 2 (FRMPD2); FRMPD2, also termed PDZ domain-containing protein 4 (PDZK4), or PDZ domain-containing protein 5C (PDZD5C), is a potential scaffold protein involved in basolateral membrane targeting in epithelial cells. It interacts with nucleotide-binding oligomerization domain-2 (NOD2) through leucine-rich repeats and forms a complex with the membrane-associated protein ERBB2IP. FRMPD2 contains an N-terminal KIND domain, a FERM domain and three PDZ domains. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1334928349  28 EYTCTIQrdAKGQYLFDLLCHHLNLLEKDYFGIR--------FVDPDKQRHWL--EFTKSVVKQLRSQPPFTMCFRVKFY 97
Cdd:cd17196    15 EVKCDIK--SRVRDVFNMVVAFANLVEHFYFGLAymkgkeffFLDHETKLHKVapEGWKDQSKKKTSIVNFTLFLRIKFF 92

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gi 1334928349  98 PAD 100
Cdd:cd17196    93 VDN 95