Gab1 [Neurosurgery Wiki]

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====== Gab1 ======

[[Grb2]]-associated binding 1 ([[Gab1]]) expression and microRNA-29a-3p ("miR-29a-3p") expression in human [[glioma cell]]s and [[tissue]]s were tested by [[Western blot]]ting [[assay]] and q[[RT-PCR]] assay. [[shRNA]]/[[siRNA]] strategy was applied to silence Gab1 in human glioma cells. miR-29a or anti-sense miR-29a construct was transfected to human glioma cells. [[Cell proliferation]] was tested by [[BrdU]] [[ELISA]] assay and [[cell counting]] assay.

Shao et al., from the 
Department of Neurosurgery, the Third Affiliated Hospital of Soochow University, [[Changzhou]], [[China]] show that expression of Gab1 was significantly elevated in human [[glioma]] tissues and [[cell]]s, which correlated with [[downregulation]] of its putative [[microRNA]]: miR-29a-3p. In [[A172]] glioma cells and primary human glioma cells, Gab1 shRNA/siRNA inhibited [[Akt]]-[[Erk]] activation and cell proliferation. Forced-expression of miR-29a-3p downregulated Gab1, inhibiting glioma cell proliferation, whereas miR-29a-3p was in-effective on cell proliferation in Gab1-silenced A172 cells. Furthermore, introduction of a 3'-untranslated region (3'-UTR) mutant Gab1 (UTR-G160A) blocked miR-29a-3p-induced inhibition on Akt signaling and A172 cell proliferation.

miR-29a-3p downregulation leads to Gab1 upregulation to promote glioma cell proliferation
((Shao NY, Wang DX, Wang Y, Li Y, Zhang ZQ, Jiang Q, Luo W, Cao C.
MicroRNA-29a-3p Downregulation Causes Gab1 Upregulation to Promote Glioma Cell
Proliferation. Cell Physiol Biochem. 2018 Jul 17;48(2):450-460. doi:
10.1159/000491776. [Epub ahead of print] PubMed PMID: 30016785.
)).
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Pediatric meningiomas share certain phenotypic and cytogenetic characteristics with adult counterparts, but GAB and stathmin co-expression in the majority of cases and non-significant difference in frequency of 1p/14q co-deletion between low- and high-grade meningiomas indicate an inherently aggressive nature. Characteristic AKT/SMO, KLF4/TRAF7 and pTERT genetic alterations seen in adults are distinctly absent in pediatric meningiomas
((Battu S, Kumar A, Pathak P, Purkait S, Dhawan L, Sharma MC, Suri A, Singh M,
Sarkar C, Suri V. Clinicopathological and molecular characteristics of pediatric 
meningiomas. Neuropathology. 2018 Feb;38(1):22-33. doi: 10.1111/neup.12426. Epub 
2017 Sep 13. PubMed PMID: 28901666.
)).
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Immunoprecipitation analyses with ErbB-modulated cells indicate that association between SHP-2 and Grb2-associated binder 1 (Gab1) is the critical step in the formation of the signalosome linking EGFR to NF-kappaB activation. We also show that EGFR-induced NF-kappaB activation is mediated by the PI3-kinase/Akt activation loop. Overexpression of SHP-2, Gab1, and myristoylated Akt significantly upregulated NF-kappaB transcriptional activity and DNA binding activity in glioblastoma cells. Interestingly, overexpression of either one of the two SH2 domain mutants of SHP-2, R32E or R138E, slightly reduced NF-kappaB activity relative to that of wild-type SHP-2, indicating that the SH2 domains of SHP-2 are required for EGFR-induced NF-kappaB activation. On the other hand, ectopic overexpression of either a Gab1 mutant incapable of binding to SHP-2 (Y627F) or a phosphatase-inactive SHP-2 mutant (C459S) caused a significant increase in NF-kappaB activity. Moreover, SHP-2 C459S-expressing cells displayed higher Gab1 phosphotyrosine content, suggesting that SHP-2 regulates Gab1 phosphorylation through its phosphatase domain, which confers a negative regulatory effect on NF-kappaB activity. These results indicate that SHP-2/Gab1 association is critical for linking EGFR to NF-kappaB transcriptional activity via the PI3-kinase/Akt signaling axis in glioblastoma cells and that SHP-2 acts as a dual regulator of NF-kappaB activation
((Kapoor GS, Zhan Y, Johnson GR, O'Rourke DM. Distinct domains in the SHP-2
phosphatase differentially regulate epidermal growth factor receptor/NF-kappaB
activation through Gab1 in glioblastoma cells. Mol Cell Biol. 2004
Jan;24(2):823-36. PubMed PMID: 14701753; PubMed Central PMCID: PMC343802.
)).