Title:RhoGEFs in Cell Motility: Novel Links Between Rgnef and Focal Adhesion Kinase
Volume: 14
Issue: 2
Author(s): N.L.G. Miller, E.G. Kleinschmidt and D.D. Schlaepfer
Affiliation:
Keywords:
Cell motility, Dbl-related GEF, FAK, integrin signaling, Rgnef/ARHGEF28, RhoGTPase.
Abstract: Rho guanine exchange factors (GEFs) are a large, diverse family of proteins defined by their ability
to catalyze the exchange of GDP for GTP on small GTPase proteins such as Rho family members. GEFs act
as integrators from varied intra- and extracellular sources to promote spatiotemporal activity of Rho GTPases
that control signaling pathways regulating cell proliferation and movement. Here we review recent studies
elucidating roles of RhoGEF proteins in cell motility. Emphasis is placed on Dbl-family GEFs and connections
to development, integrin signaling to Rho GTPases regulating cell adhesion and movement, and how these
signals may enhance tumor progression. Moreover, RhoGEFs have additional domains that confer distinctive
functions or specificity. We will focus on a unique interaction between Rgnef (also termed Arhgef28 or
p190RhoGEF) and focal adhesion kinase (FAK), a non-receptor tyrosine kinase that controls migration
properties of normal and tumor cells. This Rgnef-FAK interaction activates canonical GEF-dependent RhoA
GTPase activity to govern contractility and also functions as a scaffold in a GEF-independent manner to
enhance FAK activation. Recent studies have also brought to light the importance of specific regions within the
Rgnef pleckstrin homology (PH) domain for targeting the membrane. As revealed by ongoing Rgnef-FAK
investigations, exploring GEF roles in cancer will yield fundamental new information on the molecular
mechanisms promoting tumor spread and metastasis.
