Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To screen candidate molecules that might be useful as diagnostic biomarkers or for development of novel molecular-targeting therapies, we previously carried out gene-expression profile analysis of 101 lung carcinomas and detected an elevated expression of FGFR1OP (fibroblast growth factor receptor 1 oncogene partner) in the majority of lung cancers. Immunohistochemical staining using tumor tissue microarrays consisting of 372 archived non-small cell lung cancer (NSCLC) specimens revealed positive staining of FGFR1OP in 334 (89.8%) of 372 NSCLCs. We also found that the high level of FGFR1OP expression was significantly associated with shorter tumor-specific survival times (P < 0.0001 by log-rank test). Moreover, multivariate analysis determined that FGFR1OP was an independent prognostic factor for surgically treated NSCLC patients (P < 0.0001). Treatment of lung cancer cells, in which endogenous FGFR1OP was overexpressed, using FGFR1OP siRNA, suppressed its expression and resulted in inhibition of the cell growth. Furthermore, induction of FGFR1OP increased the cellular motility and growth-promoting activity of mammalian cells. To investigate its function, we searched for FGFR1OP-interacting proteins in lung cancer cells and identified ABL1 (Abelson murine leukemia viral oncogene homolog 1) and WRNIP1 (Werner helicase interacting protein 1), which was known to be involved in cell cycle progression. FGFR1OP significantly reduced ABL1-dependent phosphorylation of WRNIP1 and resulted in the promotion of cell cycle progression. Because our data imply that FGFR1OP is likely to play a significant role in lung cancer growth and progression, FGFR1OP should be useful as a prognostic biomarker and probably as a therapeutic target for lung cancer.
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PMID:Fibroblast growth factor receptor 1 oncogene partner as a novel prognostic biomarker and therapeutic target for lung cancer. 1788 34

PTPN6 (SHP1) is a tyrosine phosphatase that negatively controls the activity of multiple signaling pathways including STAT signaling, however role of mutated PTPN6 is not much known. Here we investigated whether PTPN6 might also be a potential target for diffuse large B cell lymphoma (DLBCL) and performed Sanger sequencing of the PTPN6 gene. We have identified missense mutations within PTPN6 (N225K and A550V) in 5% (2/38) of DLBCL tumors. Site directed mutagenesis was performed to mutate wild type (WT) PTPN6 and stable cell lines were generated by lentiviral transduction of PTPN6(WT), PTPN6(N225K) and PTPN6(A550V) constructs, and effects of WT or mutated PTPN6 on STAT3 signaling were analyzed. WT PTPN6 dephosphorylated STAT3, but had no effect on STAT1, STAT5 or STAT6 phosphorylation. Both PTPN6 mutants were unable to inhibit constitutive, as well as cytokines induced STAT3 activation. Both PTPN6 mutants also demonstrated reduced tyrosine phosphatase activity and exhibited enhanced STAT3 transactivation activity. Intriguingly, a lack of direct binding between STAT3 and WT or mutated PTPN6 was observed. However, compared to WT PTPN6, cells expressing PTPN6 mutants exhibited increased binding between JAK3 and PTPN6 suggesting a more dynamic interaction of PTPN6 with upstream regulators of STAT3. Consistent with this notion, both the mutants demonstrated increased resistance to JAK3 inhibitor, WHIP-154 relative to WT PTPN6. Overall, this is the first study, which demonstrates that N225K and A550V PTPN6 mutations cause loss-of-function leading to JAK3 mediated deregulation of STAT3 pathway and uncovers a mechanism that tumor cells can use to control PTPN6 substrate specificity.
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PMID:Loss of function mutations in PTPN6 promote STAT3 deregulation via JAK3 kinase in diffuse large B-cell lymphoma. 2656 11