Abstract
RhoA controls changes in cell morphology and invasion associated with cancer phenotypes. Cell lines derived from melanoma tumors at varying stages revealed that RhoA is selectively activated in cells of metastatic origin. We describe a functional proteomics strategy to identify proteins regulated by RhoA and report a previously uncharacterized human protein, named “mediator of RhoA-dependent invasion (MRDI),” that is induced in metastatic cells by constitutive RhoA activation and promotes cell invasion. In human melanomas, MRDI localization correlated with stage, showing nuclear localization in nevi and early stage tumors and cytoplasmic localization with plasma membrane accentuation in late stage tumors. Consistent with its role in promoting cell invasion, MRDI localized to cell protrusions and leading edge membranes in cultured cells and was required for cell motility, tyrosine phosphorylation of focal adhesion kinase, and modulation of actin stress fibers. Unexpectedly MRDI had enzymatic function as an isomerase that converts the S-adenosylmethionine catabolite 5-methylribose 1-phosphate into 5-methylribulose 1-phosphate. The enzymatic function of MRDI was required for methionine salvage from S-adenosylmethionine but distinct from its function in cell invasion. Thus, mechanisms used by signal transduction pathways to control cell movement have evolved from proteins with ancient function in amino acid metabolism.
Highlights
RhoA controls changes in cell morphology and invasion associated with cancer phenotypes
Lines—We monitored the activation of RhoA in 20 melanocyte or melanoma cell lines cultured from radial growth phase, vertical growth phase, or metastatic tumors that had been catalogued with respect to tumor pathology, tumorigenicity, and soft agar growth (18 –21)
The results indicate that RhoA is activated in cells derived from human metastatic melanomas
Summary
RhoA controls changes in cell morphology and invasion associated with cancer phenotypes. Consistent with its role in promoting cell invasion, MRDI localized to cell protrusions and leading edge membranes in cultured cells and was required for cell motility, tyrosine phosphorylation of focal adhesion kinase, and modulation of actin stress fibers. Rho GTPases control a wide range of cellular responses including cell movement, morphogenesis, and coordinated migration [3]. These pathways are implicated in malignant cell transformation and metastasis based on in vitro evidence showing tumorigenic and invasive responses to enhanced signaling in cell lines. Studies of cultured melanoma cells have revealed an “amoeboid” invasion mechanism involving RhoA-dependent Rhoactivated kinase activation and inactivation of Rac [12, 13]. The mechanisms by which Rho GTPases control FAK are incompletely understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
