Disease relevance of PSTPIP1

• PSTPIP1, mutated in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne, interacts both with pyrin and a protein tyrosine phosphatase to regulate innate and adaptive immune responses [1].
• This CD2BP1-mediated biochemical pathway(s) may function in common inflammatory disorders with apparent etiological overlap, such as rheumatoid arthritis and inflammatory bowel disease [2].
• HPIP levels are decreased in (V600E)B-RAF-transformed mouse melanocytes, suggesting that HP1beta-mediated suppressive mechanisms correlate with melanoma oncogenesis [3].

High impact information on PSTPIP1

• A search for c-Abl interacting proteins resulted in the recovery of PSTPIP1, originally identified as a binding protein of the PEST-type protein tyrosine phosphatases (PTP) [4].
• In (-/-) cells, we found a significant increase in the level of tyrosine phosphorylation of PSTPIP, a cleavage furrow-associated protein that interacts physically with all PEST family members [5].
• Expression of CD2BP1 is restricted to hematopoietic tissue, being prominent in T and natural killer (NK) cells, with long (CD2BP1L) and short (CD2BP1S) variants arising by alternative RNA splicing [6].
• PSTPIP: a tyrosine phosphorylated cleavage furrow-associated protein that is a substrate for a PEST tyrosine phosphatase [7].
• Overexpression of PSTPIP in 3T3 cells resulted in the formation of extended filopodia, consistent with a role for this protein in actin reorganization [7].

Biological context of PSTPIP1

• The Y344F PSTPIP1/CD2BP1 mutation, which blocks tyrosine phosphorylation, was associated with a marked reduction in pyrin binding in pervanadate-treated cells [8].
• Confirmatory PCR and FISH mapping of the der(15) showed loss of chromosome material proximal to the breakpoint on chromosome 15, containing the PSTPIP1 and RCN2 genes [9].
• A membrane-proximal proline-rich tandem repeat, involved in cytokine production, is recognized by the intracellular CD2 binding protein CD2BP2 [10].
• Biochemical and RNA-interference studies demonstrated that HPIP influences ERalpha-dependent rapid estrogen signaling by acting as a scaffold protein and recruits Src kinase and the p85 subunit of phosphatidylinositol 3-kinase to a complex with ERalpha, which in turn stimulates AKT and MAPK [11].
• Here we show that interleukin (IL)-6 regulates the methyltransferase promoter and resulting enzyme activity, which requires transcriptional activation by the Fli-1 transcription factor (Spyropoulos, D. D., Pharr, P. N., Lavenburg, K. R., Jackers, P., Papas, T. S., Ogawa, M., and Watson, D. K. (1998) Mol. Cell. Biol. 15, 5643-5652) [12].

Anatomical context of PSTPIP1

• Consistent with the hypothesis that these mutations exert a dominant-negative effect on the previously reported activity of pyrin, we found increased IL-1beta production by peripheral blood leukocytes from a clinically active PAPA patient with the A230T PSTPIP1/CD2BP1 mutation and in cell lines transfected with both PAPA-associated mutants [8].
• Recently, PSTPIP1/CD2BP1 mutations were shown to cause the syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), a dominantly inherited autoinflammatory disorder mediated predominantly by granulocytes [8].
• Endogenous PSTPIP1/CD2BP1 and pyrin are coexpressed in monocytes and granulocytes and can be coimmunoprecipitated from THP-1 cells [8].
• These data suggest that the PSTPIP and WASP interaction is regulated by tyrosine phosphorylation of the PSTPIP SH3 domain, and this binding event may control aspects of the actin cytoskeleton [13].
• We previously observed a defect in cytokinesis and an increase in the tyrosine phosphorylation of PSTPIP in PTP-PEST-deficient fibroblasts [14].

Associations of PSTPIP1 with chemical compounds

• Here we report the identification of the Src homology 3 domain-containing adaptor protein PSTPIP as a FasL-interacting partner, which binds to the proline-rich domain [15].
• Identification of a novel polyproline recognition site in the cytoskeletal associated protein, proline serine threonine phosphatase interacting protein [16].
• Migration of HPIP from water into vesicles involves rupture of hydrogen (H) bonds with water and formation of an internal H bond once the probe is inside the vesicle [17].
• The cyclic 1,1-dimethyl-4-acetylpiperazinium iodide (HPIP) molecule was previously shown to be a strong agonist for nicotinic acetylcholine receptors (McGroddy et al., 1993), while the acyclic N,N,N,N'-tetramethyl-N'-acetylethylenediamine iodide (HTED) derivative is much less potent [18].
• These are [Zn(3)(p-BDC)(4)].2HPIP, 2 (HPIP is partly protonated piperazine), and [Zn(3)(p-BDC)(3)(H(2)BDC)].(C(6)H(15)NO).H(2)O.3DMF, 3 (C(6)H(15)NO is triethylamine N-oxide) [19].

Physical interactions of PSTPIP1

• Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder [2].

Regulatory relationships of PSTPIP1

• Because of their high binding affinity to pyrin's B-box, PAPA-associated PSTPIP1 mutants were found to be more effective than WT PSTPIP1 in inducing pyrin activation [20].

Other interactions of PSTPIP1

• PAPA-associated A230T and E250Q PSTPIP1/CD2BP1 mutations markedly increased pyrin binding as assayed by immunoprecipitation and, relative to WT, these mutants were hyperphosphorylated when coexpressed with c-Abl kinase [8].
• We have now established this by the identification of co-segregating disease-causing mutations in the CD2-binding protein 1 (CD2BP1; GenBank accession no XM 044569) gene in the two reported families with this disorder [2].
• An intracellular protein termed CD2 binding protein 2 (CD2BP2), which binds to a site containing two PPPGHR segments within the cytoplasmic region of CD2, was identified [21].
• CD2BP1 and CARD15 mutations are not associated with pyoderma gangrenosum in patients with inflammatory bowel disease [22].
• An intracellular CD2 binding protein, CD2BP2, interacts with two tandem PPPPGHR segments of the CD2 tail [23].

Analytical, diagnostic and therapeutic context of PSTPIP1

• Confocal microscopy revealed that PSTPIP 2 colocalizes with PSTPIP in F actin-rich regions [24].

References