Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.10.1 (
ERK
)
95,504
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Despite abundant data supporting c-Src as a metastasis-promoting oncogene, activating mutations of c-Src are rare. This suggests that trans-interacting proteins may have a critical role in regulating c-Src activation. Here, we first report the discovery of Src homology 3 (SH3) domain-binding glutamic acid-rich-like protein (
SH3BGRL
), a novel c-Src activator in mice. Ectopic expression of murine
SH3BGRL
(mSH3BGRL) strongly promoted both tumor cell invasion and lung metastasis. Molecularly, mSH3BGRL specifically bound the inactive form of c-Src phosphorylated at Tyr527, promoting Tyr416 phosphorylation of c-Src and subsequent FAK-mediated activation of
ERK
and AKT signaling pathways. Targeting endogenous c-Src alone was sufficient to abolish mSH3BGRL-induced cancer metastasis in vivo. Unexpectedly, human
SH3BGRL
(hSH3BGRL) in turn suppressed tumorigenesis and metastasis in nature. We attempted site-specific reversion of hSH3BGRL amino-acid sequence to mSH3BGRL and found V108A substitution sufficient to restore
SH3BGRL
function as a c-Src activator and metastasis promoter. Notably, the somatic mutation R76C of hSH3BGRL can similarly act as hSH3BGRL-V108A and mSH3BGRL in tumorigenesis and metastasis. Our results uncover an evolutionarily controversial role of
SH3BGRL
in driving tumor metastasis through c-Src activation, and suggests that hSH3BGRL mutation status could be relevant to cancer diagnosis and therapy.
...
PMID:Dual-faced SH3BGRL: oncogenic in mice, tumor suppressive in humans. 2645 18
Exploring
ERBB2
-related pathways will help us finding sensitive molecules and potential combined therapeutic targets of
ERBB2
-targeted therapy for ERBB2+ gastric cancer (GC). In this study, we performed a cross-databases study focused on ERBB2+ GC. The data of ERBB2+ GC deposited in the cancer genome atlas (TCGA), gene expression omnibus (GEO), InBio Map
TM
, cancer cell line encyclopedia (CCLE), and cancer therapeutics response portal (CTRP) were analyzed. The correlation of expression levels of candidate and IC50 of candidate genes-targeted drugs were verified on NCI-N87 and MKN-45 GC cell lines. We found that RARA, THRA, CACNB1, and TOP2A are drug sensitive biomarkers of
ERBB2
-targeted treatment with FDA-approved drugs. All these genes act through Myc signaling pathway. Myc is the downstream hub gene of both
ERBB2
and RARA. The expression of RARA, THRA, and CACNB1 were negatively correlated with Myc activation, while
ERBB2
and TOP2A positively correlated with Myc activation. SH3BGRL3,
SH3BGRL
, and NRG2 were identified as potential ligands of
ERBB2
. The ERBB2+ GC with RARA amplification demonstrated better prognosis than those without RARA amplification, while overexpression of NRG2 and
SH3BGRL
correlated with poor prognosis in ERBB2+ GC. About 90% of ERBB2+ GC was compatible with chromosome instability (CIN) subtype of TCGA, which overlaps with intestinal-type GC in Lauren classification. In validating experiments, combination of Lapatinib and all-trans retinoic acid (ATRA) synergistically suppresses cell growth, and accompanied by decreased expression of MYC. In conclusions, we identified several predicting biomarkers for
ERBB2
-targeted therapy and corresponding histological features of ERBB2+ GC. Combination of
ERBB2
antagonist or RARA agonist may be effective synergistic regimens for ERBB2+ GC.
...
PMID:Cross-Database Analysis Reveals Sensitive Biomarkers for Combined Therapy for ERBB2+ Gastric Cancer. 3012 34
