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GPRC5A directly inhibits EGFR signaling to suppress lung tumorigenesis

 

G protein coupled receptor family C group 5 type A (GPRC5A) is predominately expressed in lung tissue. Previous studies have reported Gprc5a gene knockout (ko) (Gprc5a-/-) mice appeared to have normal lung, but spontaneously developed lung cancer in about 1.5 to 2 years, indicating the tumor suppressor role of GPRC5A. However, the molecular mechanism underlying the tumor suppress effect of GPRC5A remains elusive. Zhong et al. revealed that GPRC5A negatively regulates EGFR signaling and its downstream signaling STAT3. The article was published in Cancer Research.

 

EGFR, belongs to the ERBB family, is triggered by EGF binding for homodimerization or heterodimerization with other ERBB members, subsequently phosphorylates and activates downstream effectors including ERK/MAPK, PI3K/AKT, and STAT3. In this study, mouse tracheal epichelial cells (MTEC) from mice had an increased level of EGFR and downstream STAT3 compared with wild type mice. On the other hand, GPRC5A expression inhibited EGFR and STAT3 signaling. Mechanically, GPRC5A binds to EGFR on its transmembrane domain for inhibition of EGFR activities. In human non-small cell lung carcinoma cells, overexpression of GPRC5A inhibits both EGF-induced and constitutively activated EGFR signaling. These findings reveal the mechanism of the induction of EGFR and STAT3 aberrant signaling by GPRC5A deficiency. 

 

Reference:
Cancer Res. 2015 Mar 5. pii: canres.2005.2014.

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