Melanoma Inhibitory Activity-Like protein; MIAL is specifically expressed in the cochlea and the vestibule of the inner ear and may contribute to inner ear dysfunction in humans. MIAL is a member of the recently identified family that also includes MIA, MIA2, and MIA3 (also called TANGO); MIA is the most studied member of the family. MIA is a single domain protein that adopts a Src Homology 3 (SH3) domain-like fold; it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. MIA is secreted from malignant melanoma cells and it plays an important role in melanoma development and invasion. MIA is expressed by chondrocytes in normal tissues and may be important in the cartilage cell phenotype. Unlike classical SH3 domains, MIA does not bind proline-rich ligands.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 10181138  31 LCADEECVYTISLARAQEDYNAPDCRFIDVKKGQQIYVYSKLVTENGAGEFWAGSVYGDH-QDEMGIVGYFPSNLVKEQR 109
Cdd:cd11891   1 LCADEECVYAISLARAEDDYNAPDCRFINIKKGQLIYVYSKLVKENGAGEFWSGSVYSERyVDQMGIVGYFPSNLVKEQT 80

                ...
gi 10181138 110 VYQ 112
Cdd:cd11891  81 VYK 83

Melanoma Inhibitory Activity-Like protein; MIAL is specifically expressed in the cochlea and the vestibule of the inner ear and may contribute to inner ear dysfunction in humans. MIAL is a member of the recently identified family that also includes MIA, MIA2, and MIA3 (also called TANGO); MIA is the most studied member of the family. MIA is a single domain protein that adopts a Src Homology 3 (SH3) domain-like fold; it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. MIA is secreted from malignant melanoma cells and it plays an important role in melanoma development and invasion. MIA is expressed by chondrocytes in normal tissues and may be important in the cartilage cell phenotype. Unlike classical SH3 domains, MIA does not bind proline-rich ligands.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 10181138  31 LCADEECVYTISLARAQEDYNAPDCRFIDVKKGQQIYVYSKLVTENGAGEFWAGSVYGDH-QDEMGIVGYFPSNLVKEQR 109
Cdd:cd11891   1 LCADEECVYAISLARAEDDYNAPDCRFINIKKGQLIYVYSKLVKENGAGEFWSGSVYSERyVDQMGIVGYFPSNLVKEQT 80

                ...
gi 10181138 110 VYQ 112
Cdd:cd11891  81 VYK 83

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 10181138     44 ARAQEDYNAPDCRFIDVKKGQQIYVYSKLVtengaGEFWAGSVYGdhqdemGIVGYFPSNLVK 106
Cdd:smart00326   5 VRALYDYTAQDPDELSFKKGDIITVLEKSD-----DGWWKGRLGR------GKEGLFPSNYVE 56

Melanoma Inhibitory Activity-Like protein; MIAL is specifically expressed in the cochlea and the vestibule of the inner ear and may contribute to inner ear dysfunction in humans. MIAL is a member of the recently identified family that also includes MIA, MIA2, and MIA3 (also called TANGO); MIA is the most studied member of the family. MIA is a single domain protein that adopts a Src Homology 3 (SH3) domain-like fold; it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. MIA is secreted from malignant melanoma cells and it plays an important role in melanoma development and invasion. MIA is expressed by chondrocytes in normal tissues and may be important in the cartilage cell phenotype. Unlike classical SH3 domains, MIA does not bind proline-rich ligands.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 10181138  31 LCADEECVYTISLARAQEDYNAPDCRFIDVKKGQQIYVYSKLVTENGAGEFWAGSVYGDH-QDEMGIVGYFPSNLVKEQR 109
Cdd:cd11891   1 LCADEECVYAISLARAEDDYNAPDCRFINIKKGQLIYVYSKLVKENGAGEFWSGSVYSERyVDQMGIVGYFPSNLVKEQT 80

                ...
gi 10181138 110 VYQ 112
Cdd:cd11891  81 VYK 83

Melanoma Inhibitory Activity protein; MIA is a single domain protein that adopts a Src Homology 3 (SH3) domain-like fold; it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. MIA is secreted from malignant melanoma cells and it plays an important role in melanoma development and invasion. MIA is expressed by chondrocytes in normal tissues and may be important in the cartilage cell phenotype. Unlike classical SH3 domains, MIA does not bind proline-rich ligands. It binds peptide ligands with sequence similarity to type III human fibronectin repeats.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 10181138  29 KKLCADEECVYTISLARAQEDYNAPDCRFIDVKKGQQIYVYSKLvteNGAGE-FWAGSVYGDHQDEMGI-VGYFPSNLVK 106
Cdd:cd11890   1 KKLCADQECSHPISIAVALQDYMAPDCRFIPIQRGQVVYVFSKL---KGRGRlFWGGSVQGDYYGEQAArLGYFPSSIVQ 77

                        90       100
                ....*....|....*....|.
gi 10181138 107 EQRVYQEATKEIPTTDIDFFC 127
Cdd:cd11890  78 EDQYLKPGKVEVKTDKWDFYC 98

Src Homology 3 domain of Melanoma Inhibitory Activity 3 protein; MIA3, also called TANGO or TANGO1, acts as a tumor suppressor of malignant melanoma. It is downregulated or lost in melanoma cells lines. Unlike other MIA family members, MIA3 is widely expressed except in hematopoietic cells. MIA3 is an ER resident transmembrane protein that is required for the loading of collagen VII into transport vesicles. SNPs in the MIA3 gene have been associated with coronary arterial disease and myocardial infarction. MIA3 contains an N-terminal SH3-like domain, similar to MIA. It is a member of the recently identified family that also includes MIA, MIAL, and MIA2. MIA is a single domain protein that adopts a SH3 domain-like fold; it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. Unlike classical SH3 domains, MIA does not bind proline-rich ligands.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 10181138  31 LCADEECVYTISLARAQEDYNAPDCRFIDVKKGQQIYVYSKLVteNGAGEFWAGSVYGDhqdemgiVGYFPSNLVKEQRV 110
Cdd:cd11893   1 RCADEECSMLLCRGKAVKDFTGPDCRFLSFKKGETIYVYYKLS--GRRTDLWAGSVGFD-------FGYFPKDLLDVNHL 71

                .
gi 10181138 111 Y 111
Cdd:cd11893  72 Y 72

C-terminal (or second) Src homology 3 domain of VAV proteins; VAV proteins function both as cytoplasmic guanine nucleotide exchange factors (GEFs) for Rho GTPases and scaffold proteins and they play important roles in cell signaling by coupling cell surface receptors to various effector functions. They play key roles in processes that require cytoskeletal reorganization including immune synapse formation, phagocytosis, cell spreading, and platelet aggregation, among others. Vertebrates have three VAV proteins (VAV1, VAV2, and VAV3). VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 10181138  44 ARAQEDYNAPDCRFIDVKKGQQIYVYSKLvtenGAGEFWAGSVYGDhqdemgiVGYFPSNLVKE 107
Cdd:cd11830   2 AKARYDFCARDMRELSLKEGDVVKIYNKK----GQQGWWRGEINGR-------IGWFPSTYVEE 54

C-terminal (or second) Src homology 3 domain of VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The C-terminal SH3 domain of Vav1 interacts with a wide variety of proteins including cytoskeletal regulators (zyxin), RNA-binding proteins (Sam68), transcriptional regulators, viral proteins, and dynamin 2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 10181138  44 ARAQEDYNAPDCRFIDVKKGQQIyvysKLVTENGAGEFWAGSVYGDhqdemgiVGYFPSNLVKE 107
Cdd:cd11976   2 AKARYDFCARDRSELSLKEGDII----KILNKKGQQGWWRGEIYGR-------VGWFPANYVEE 54

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 10181138  44 ARAQEDYNAPDCRFIDVKKGQQIYVYSKlvtenGAGEFWAGSVYGdhqdemGIVGYFPSN 103
Cdd:cd00174   2 ARALYDYEAQDDDELSFKKGDIITVLEK-----DDDGWWEGELNG------GREGLFPAN 50

Src Homology 3 domain of Mixed Lineage Kinases; MLKs are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Mammals have four MLKs (MLK1-4), mostly conserved in vertebrates, which contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 10181138  46 AQEDYNAPDCRFIDVKKGQQIYVYSKLVTENGAGEFWAGSVygdhQDEMGIvgyFPSNLVKE 107
Cdd:cd11876   4 ALFDYDARGEDELTLRRGQPVEVLSKDAAVSGDEGWWTGKI----GDKVGI---FPSNYVAP 58