Alternative titles; symbols
HGNC Approved Gene Symbol: PSTPIP1
SNOMEDCT: 724015007; ICD10CM: M04.8;
Cytogenetic location: 15q24.3 Genomic coordinates (GRCh38): 15:76,994,680-77,037,475 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q24.3 | Pyogenic sterile arthritis, pyoderma gangrenosum, and acne | 604416 | Autosomal dominant | 3 |
Spencer et al. (1997) identified mouse Pstpip1 as a binding protein of the PEST-type protein tyrosine phosphatases (PTPs, e.g., PTP-PEST; 600079).
Using a yeast 2-hybrid screen of a T-cell cDNA library with the cytoplasmic tail of CD2 (186990) as bait, followed by probing a T-cell cDNA library, Li et al. (1998) isolated cDNAs encoding splice variants of human PSTPIP1, which they called CD2BP1. The full-length 417-amino acid protein, which is 88% identical to mouse Pstpip1, contains a coiled-coil region, which is 30% identical to yeast Cdc15, a PEST region, and a C-terminal SH3 domain. Compared with full-length CD2BP1, the shorter variant has a 19-amino acid deletion. Northern blot analysis revealed expression of a 1.9-kb CD2BP1 transcript that was restricted to hemopoietic tissues and cell lines, with expression upregulated in activated T cells. Immunoprecipitation analysis showed expression of a 50-kD protein. Fluorescence microscopy demonstrated localization of CD2BP1 at the interface of the cytosol and the plasma membrane and colocalization with CD2 after ligand-induced clustering of surface CD2.
Binding analysis by Li et al. (1998) showed that the CD2BP1 SH3 domain interacts with proline-rich segments of the CD2 cytoplasmic tail. Functional analysis indicated a lack of kinase activity, but significant tyrosine phosphatase activity.
Using a yeast 2-hybrid screen, Cong et al. (2000) identified mouse Pstpip1 as an ABL (189980)-interacting protein. They showed that Pstpip1 was phosphorylated by ABL. Growth factor-induced Pstpip1 phosphorylation was diminished in ABL null fibroblasts. Pstpip1 was able to bridge ABL to the PEST-type PTPs. Several experiments suggested that the PEST-type PTPs negatively regulate ABL activity: ABL was hyperphosphorylated in PTP-PEST-deficient cells; disruption of the ABL-Pstpip1-PEST-type PTP ternary complex by overexpression of mutants increased ABL phosphotyrosine content; and PDGF (see 190040)-induced ABL kinase activation was prolonged in PTP-PEST-deficient cells. The authors concluded that dephosphorylation of ABL by PSTPIP1-directed PEST-type PTPs represents a novel mechanism by which ABL activity is regulated.
Using a yeast 2-hybrid assay, Shoham et al. (2003) showed that human PSTPIP1 and human pyrin (MEFV; 608107) interacted with each other and colocalized within peripheral blood granulocytes and monocytes. Tyrosine phosphorylation of PSTPIP1 markedly increased binding to pyrin. Expression of 2 PSTPIP1 mutations (606347.0001 and 606347.0002) associated with PAPA syndrome (604416) resulted in increased PSTPIP1-pyrin binding. Shoham et al. (2003) suggested that sequestration of pyrin in PAPA syndrome may prevent pyrin's normal immunoregulatory functions, resulting in an excess of IL1-beta (147720) production, as found in a patient with PAPA syndrome. The findings elucidated another pathway involved in regulating inflammation, and linked PAPA syndrome and familial Mediterranean fever (FMF; 249100) as disorders arising from defects within the same pathway.
Yu et al. (2007) found that both pyrin and PSTPIP1 formed homotrimers, and that the pyrin homotrimer was inactive due to masking of its PYD motif by its B box. PSTPIP1 activated pyrin by binding to its B box and unmasking the PYD, leading to interaction of the PYD with ASC (PYCARD; 606838), ASC dimerization, and recruitment and activation of caspase-1 (CASP1; 147678), a proinflammatory enzyme. Autoinflammatory PSTPIP1 mutants had higher binding affinities for the pyrin B box than did wildtype PSTPIP1.
Gross (2015) mapped the PSTPIP1 gene to chromosome 15q24.3 based on an alignment of the PSTPIP1 sequence (GenBank AF038603) with the genomic sequence (GRCh38).
Yeon et al. (2000) localized the genes for PAPA syndrome (604416) and familial recurrent arthritis to chromosome 15q and suggested that they are the same disorder. Wise et al. (2002) identified mutations in the PSTPIP1 gene in 2 reported families with this disorder. E250Q (606347.0001) or A230T (606347.0002) amino acid substitutions occurred within a domain highly homologous to yeast cleavage furrow-associated protein CDC15. PSTPIP1 and its murine ortholog are adaptor proteins known to interact with PEST-type PTPs such as PTPN12 (600079). Yeast 2-hybrid assays demonstrated severely reduced binding between PTPN12 and both the E250Q and A230T mutant proteins. Previous evidence supported the integral role of PSTPIP1 and its interacting proteins in actin reorganization during cytoskeletal-mediated events. The authors hypothesized that the disease-causing mutations identified compromise physiologic signaling necessary for the maintenance of a proper inflammatory response.
In a 4-generation family with familial recurrent arthritis, which was thought to be the same disorder as PAPA syndrome (604416), Wise et al. (2002) identified a 964G-C transversion in the PSTPIP1 gene, which was predicted to result in a glu250-to-gln (E250Q) substitution. Yeast 2-hybrid assays demonstrated severely reduced binding between PTPN12 and the mutant protein.
In affected sibs with PAPA syndrome (604416), Wise et al. (2002) identified a 904G-A transition in the PSTPIP1 gene, which was predicted to result in an ala230-to-thr (A230T) substitution. Yeast 2-hybrid assays demonstrated severely reduced binding between PTPN12 and the mutant protein.
Cong, F., Spencer, S., Cote, J.-F., Wu, Y., Tremblay, M. L., Lasky, L. A., Goff, S. P. Cytoskeletal protein PSTPIP1 directs the PEST-type protein tyrosine phosphatase to the c-Abl kinase to mediate Abl dephosphorylation. Molec. Cell 6: 1413-1423, 2000. [PubMed: 11163214] [Full Text: https://doi.org/10.1016/s1097-2765(00)00138-6]
Gross, M. B. Personal Communication. Baltimore, Md. 2/17/2015.
Li, J., Nishizawa, K., An, W., Hussey, R. E., Lialios, F. E., Salgia, R., Sunder-Plassmann, R., Reinherz, E. L. A cdc15-like adaptor protein (CD2BP1) interacts with the CD2 cytoplasmic domain and regulates CD2-triggered adhesion. EMBO J. 17: 7320-7336, 1998. [PubMed: 9857189] [Full Text: https://doi.org/10.1093/emboj/17.24.7320]
Shoham, N. G., Centola, M., Mansfield, E., Hull, K. M., Wood, G., Wise, C. A., Kastner, D. L. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc. Nat. Acad. Sci. 100: 13501-13506, 2003. [PubMed: 14595024] [Full Text: https://doi.org/10.1073/pnas.2135380100]
Spencer, S., Dowbenko, D., Cheng, J., Li, W., Brush, J., Utzig, S., Simanis, V., Lasky, L. A. PSTPIP: a tyrosine phosphorylated cleavage furrow-associated protein that is a substrate for PEST tyrosine phosphatase. J. Cell Biol. 138: 845-860, 1997. [PubMed: 9265651] [Full Text: https://doi.org/10.1083/jcb.138.4.845]
Wise, C. A., Gillum, J. D., Seidman, C. E., Lindor, N. M., Veile, R., Bashiardes, S., Lovett, M. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum. Molec. Genet. 11: 961-969, 2002. [PubMed: 11971877] [Full Text: https://doi.org/10.1093/hmg/11.8.961]
Yeon, H. B., Lindor, N. M., Seidman, J. G., Seidman, C. E. Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q. Am. J. Hum. Genet. 66: 1443-1448, 2000. [PubMed: 10729114] [Full Text: https://doi.org/10.1086/302866]
Yu, J.-W., Fernandes-Alnemri, T., Datta, P., Wu, J., Juliana, C., Solorzano, L., McCormick, M., Zhang, Z., Alnemri, E. S. Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants. Molec. Cell 28: 214-227, 2007. [PubMed: 17964261] [Full Text: https://doi.org/10.1016/j.molcel.2007.08.029]