Inappropriate activation of epidermal growth factor receptor (EGFR) plays a causal role in many cancers including colon cancer. The activation of EGFR by phosphorylation is balanced by receptor kinase and protein tyrosine phosphatase activities. However, the mechanisms of negative EGFR regulation by tyrosine phosphatases remain largely unexplored. Our previous results indicate that protein tyrosine phosphatase receptor type O (PTPRO) is down-regulated in a subset of colorectal cancer (CRC) patients with a poor prognosis. Here we identified PTPRO as a phosphatase that negatively regulates SRC by directly dephosphorylating Y416 phosphorylation site. SRC activation triggered by PTPRO down-regulation induces phosphorylation of both EGFR at Y845 and the c-CBL ubiquitin ligase at Y731. Increased EGFR phosphorylation at Y845 promotes its receptor activity, whereas enhanced phosphorylation of c-CBL triggers its degradation promoting EGFR stability. Importantly, hyperactivation of SRC/EGFR signaling triggered by loss of PTPRO leads to high resistance of colon cancer to EGFR inhibitors. Our results not only highlight the PTPRO contribution in negative regulation of SRC/EGFR signaling but also suggest that tumors with low PTPRO expression may be therapeutically targetable by anti-SRC therapies.

• MeSH
• buňky HT-29 MeSH
• Caco-2 buňky MeSH
• chinazoliny farmakologie   MeSH
• epidermální růstový faktor farmakologie   MeSH
• erbB receptory antagonisté a inhibitory   metabolismus   MeSH
• fosforylace MeSH
• gefitinib MeSH
• HCT116 buňky MeSH
• HEK293 buňky MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• MAP kinasový signální systém MeSH
• messenger RNA genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory tračníku farmakoterapie   enzymologie   genetika   patologie   MeSH
• protoonkogenní proteiny c-cbl metabolismus   MeSH
• signální transdukce MeSH
• skupina kinas odvozených od src-genu metabolismus   MeSH
• tyrosinfosfatasy receptorového typu, třída 3 biosyntéza   genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CBL protein, human MeSH Prohlížeč
• chinazoliny MeSH
• EGFR protein, human MeSH Prohlížeč
• epidermální růstový faktor MeSH
• erbB receptory MeSH
• gefitinib MeSH
• inhibitory proteinkinas MeSH
• messenger RNA MeSH
• protoonkogenní proteiny c-cbl MeSH
• PTPRO protein, human MeSH Prohlížeč
• skupina kinas odvozených od src-genu MeSH
• tyrosinfosfatasy receptorového typu, třída 3 MeSH

CD148 is a receptor-like protein-tyrosine phosphatase known to inhibit transduction of mitogenic signals in non-hematopoietic cells. Similarly, in the hematopoietic lineage, CD148 inhibited signal transduction downstream of T cell receptor. However, it also augmented immunoreceptor signaling in B cells and macrophages via dephosphorylating C-terminal tyrosine of Src family kinases (SFK). Accordingly, endogenous CD148 compensated for the loss of the main SFK activator CD45 in murine B cells and macrophages but not in T cells. Hypothetical explanations for the difference between T cells and other leukocyte lineages include the inability of CD148 to dephosphorylate a specific set of SFKs involved in T cell activation or the lack of CD148 expression during critical stages of T cell development. Here we describe striking differences in CD148 expression between human and murine thymocyte subsets, the only unifying feature being the absence of CD148 during the positive selection when the major developmental block occurs under CD45 deficiency. Moreover, we demonstrate that similar to CD45, CD148 has both activating and inhibitory effects on the SFKs involved in TCR signaling. However, in the absence of CD45, activating effects prevail, resulting in functional complementation of CD45 deficiency in human T cell lines. Importantly, this is independent of the tyrosines in the CD148 C-terminal tail, contradicting the recently proposed phosphotyrosine displacement model as a mechanism of SFK activation by CD148. Collectively, our data suggest that differential effects of CD148 in T cells and other leukocyte subsets cannot be explained by the CD148 inability to activate T cell SFKs but rather by its dual inhibitory/activatory function and specific expression pattern.

• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• aktivace enzymů MeSH
• antigeny CD45 nedostatek   MeSH
• fosfolipasa C gama metabolismus   MeSH
• fosforylace MeSH
• hematopoetické kmenové buňky cytologie   enzymologie   metabolismus   MeSH
• Jurkat buňky MeSH
• lidé MeSH
• membránové proteiny metabolismus   MeSH
• myši MeSH
• receptory antigenů T-buněk imunologie   metabolismus   MeSH
• regulace genové exprese enzymů MeSH
• signální transdukce * MeSH
• skupina kinas odvozených od src-genu chemie   metabolismus   MeSH
• T-lymfocyty cytologie   enzymologie   metabolismus   MeSH
• terciární struktura proteinů MeSH
• thymus cytologie   MeSH
• tyrosin metabolismus   MeSH
• tyrosinfosfatasy receptorového typu, třída 3 chemie   genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• antigeny CD45 MeSH
• fosfolipasa C gama MeSH
• LAT protein, human MeSH Prohlížeč
• membránové proteiny MeSH
• PTPRJ protein, human MeSH Prohlížeč
• receptory antigenů T-buněk MeSH
• skupina kinas odvozených od src-genu MeSH
• tyrosin MeSH
• tyrosinfosfatasy receptorového typu, třída 3 MeSH