Novel role for CRK adaptor proteins as essential components of SRC/FAK signaling for epithelial-mesenchymal transition and colorectal cancer aggressiveness.

International Journal of Cancer. Journal International Du Cancer
Fabian C FrankeKlaus-Peter Janssen

Abstract

Epithelial-mesenchymal transition (EMT) is a cell plasticity process required for metastasis and chemoresistance of carcinoma cells. We report a crucial role of the signal adaptor proteins CRK and CRKL in promoting EMT and tumor aggressiveness, as well as resistance against chemotherapy in colorectal and pancreatic carcinoma. Genetic loss of either CRKL or CRK partially counteracted EMT in three independent cancer cell lines. Strikingly, complete loss of the CRK family shifted cells strongly toward the epithelial phenotype. Cells exhibited greatly increased E-cadherin and grew as large, densely packed clusters, completely lacked invasiveness and the ability to undergo EMT induced by cytokines or genetic activation of SRC. Furthermore, CRK family-deficiency significantly reduced cell survival, proliferation and chemoresistance, as well as ERK1/2 phosphorylation and c-MYC protein levels. In accordance, MYC-target gene expression was identified as novel hallmark process positively regulated by CRK family proteins. Mechanistically, CRK proteins were identified as pivotal amplifiers of SRC/FAK signaling at focal adhesions, mediated through a novel positive feedback loop depending on RAP1. Expression of the CRK family and the EMT reg...Continue Reading

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Citations

Oct 24, 2020·ACS Combinatorial Science·Milad AshrafizadehPooyan Makvandi
Dec 31, 2020·Clinical and Translational Medicine·Shiyu LiKongming Wu
Mar 13, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jennifer JaufmannSandra Beer-Hammer
Jun 2, 2021·EMBO Molecular Medicine·Francesca CitronGustavo Baldassarre

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