Intra- and Intermolecular Interactions between Intracellular Domains of Receptor Protein-tyrosine Phosphatases

Netherlands Institute for Space Research, Utrecht, Utrecht, Utrecht, Netherlands
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2003; 277(49):47263-9. DOI: 10.1074/jbc.M205810200
Source: PubMed


The presence of two protein-tyrosine phosphatase (PTP) domains is a striking feature in most transmembrane receptor PTPs (RPTPs). The generally inactive membrane-distal PTP domains (RPTP-D2s) bind and are proposed to regulate the membrane-proximal PTP domains (RPTP-D1s). We set out to characterize the interactions between RPTP-D1s and RPTP-D2s in vivo by co-immunoprecipitation of hemagglutinin-tagged fusion proteins encoding the transmembrane domain and RPTP-D1 and myc-tagged RPTP-D2. Seven RPTPs from four different subfamilies were used: RPTPalpha, RPTPepsilon, LAR, RPTPvarsigma, RPTPdelta, CD45, and RPTP(mu). We found that RPTP-D2s bound to RPTPs with different affinities. The presence of intrinsic RPTP-D2 altered the binding specificity toward other RPTP-D2s positively or negatively, depending on the identity of the RPTPs. Furthermore, the C terminus of RPTP-D2s and the "wedge" in RPTP-D1s played a central role in binding specificity. Finally, full-length RPTPalpha and LAR heterodimerized in an oxidative stress-dependent manner. Like RPTPalpha-D2, the LAR-D2 conformation was affected by oxidative stress, suggesting a common regulatory mechanism for RPTP complex formation. Taken together, interactions between RPTP-D1s and RPTP-D2s are a common but specific mechanism that is likely to be regulated. The RPTP-D2s and the wedge structures are crucial determinants of binding specificity, thus regulating cross-talk between RPTPs.

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    • "As PTPRZ1 has been linked to protein tyrosine phosphatase activity, we first assessed the ability of PTPRZ1 to regulate tyrosine phosphorylation in the response to the ligand of PTPRZ1, PTN. PTN binding to the extracellular portion of PTPRZ1 brings two molecules into close proximity and consequently the phosphatase domains dimerize in a head-to-toe arrangement with the D2 domain of one molecule blocking the active site (D1) of the second molecule, leading to suppression of phosphatase activity [31,32]. To identify molecular targets regulated by PTPRZ1 in response to PTN, we assessed tyrosine-phosphorylated proteins using an anti-phosphotyrosine antibody by WB. "
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    • "Two of our identified genes PTPRD and BTBD12 interact with these two genes or their related pathways and may impact paclitaxel response through them. p53 decreases expression of protein tyrosine phosphatase receptor type A (PTPRA) which interacts with our candidate, PTPRD [43,44]. PTPRA and PTPRD are receptor tyrosine phosphatases, and PTPRD can dephosphorylate v-src sarcoma viral oncogene homolog (SRC), altering v-raf-1 murine leukemia viral oncogene homolog 1 (RAF-1) activation, a major pathway for paclitaxel induced apoptosis [2,6,45,46]. "
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