Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

EGFR mutation-positive patients with non-small cell lung cancer (NSCLC) respond well to treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI); however, treatment with EGFR-TKIs is not curative, owing to the presence of residual cancer cells with intrinsic or acquired resistance to this class of drugs. Additional treatment targets that may enhance the efficacy of EGFR-TKIs remain elusive. Using a CRISPR/Cas9-based screen, we identified the leucine-rich repeat scaffold protein SHOC2 as a key modulator of sensitivity to EGFR-TKI treatment. On the basis of in vitro assays, we demonstrated that SHOC2 expression levels strongly correlate with the sensitivity to EGFR-TKIs and that SHOC2 affects the sensitivity to EGFR-TKIs in NSCLC cells via SHOC2/MRAS/PP1c and SHOC2/SCRIB signaling. The potential SHOC2 inhibitor celastrol phenocopied SHOC2 depletion. In addition, we confirmed that SHOC2 expression levels were important for the sensitivity to EGFR-TKIs in vivo. Furthermore, IHC showed the accumulation of cancer cells that express high levels of SHOC2 in lung cancer tissues obtained from patients with NSCLC who experienced acquired resistance to EGFR-TKIs. These data indicate that SHOC2 may be a therapeutic target for patients with NSCLC or a biomarker to predict sensitivity to EGFR-TKI therapy in EGFR mutation-positive patients with NSCLC. Our findings may help improve treatment strategies for patients with NSCLC harboring EGFR mutations. IMPLICATIONS: This study showed that SHOC2 works as a modulator of sensitivity to EGFR-TKIs and the expression levels of SHOC2 can be used as a biomarker for sensitivity to EGFR-TKIs.
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PMID:SHOC2 Is a Critical Modulator of Sensitivity to EGFR-TKIs in Non-Small Cell Lung Cancer Cells. 3310 73

The Ras family of small GTPases comprises about 36 members in humans. M-Ras is related to classical Ras with regard to its regulators and effectors, but solely constitutes a subfamily among the Ras family members. Although classical Ras strongly binds Raf and highly activates the ERK pathway, M-Ras less strongly binds Raf and moderately but sustainedly activates the ERK pathway to induce neuronal differentiation. M-Ras also possesses specific effectors, including RapGEFs and the PP1 complex Shoc2-PP1c, which dephosphorylates Raf to activate the ERK pathway. M-Ras is highly expressed in the brain and plays essential roles in dendrite formation during neurogenesis, in contrast to the axon formation by R-Ras. M-Ras is also highly expressed in the bone and induces osteoblastic differentiation and transdifferentiation accompanied by calcification. Moreover, M-Ras elicits epithelial-mesenchymal transition-mediated collective and single cell migration through the PP1 complex-mediated ERK pathway activation. Activating missense mutations in the MRAS gene have been detected in Noonan syndrome, one of the RASopathies, and MRAS gene amplification occurs in several cancers. Furthermore, several SNPs in the MRAS gene are associated with coronary artery disease, obesity, and dyslipidemia. Therefore, M-Ras carries out a variety of cellular, physiological, and pathological functions. Further investigations may reveal more functions of M-Ras.
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PMID:M-Ras is Muscle-Ras, Moderate-Ras, Mineral-Ras, Migration-Ras, and Many More-Ras. 3313 Jan 77


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