A non-canonical role for Rgnef (p190RhoGEF) in promoting integrin-stimulated focal adhesion kinase activation

Miller, Nichol L.G.; Lawson, Christine; Kleinschmidt, Elizabeth G.; Tancioni, Isabelle; Schlaepfer, David D.

doi:10.1242/jcs.135509

Cited by 22 publications

(25 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FAK recruitment and activation at nascent FAs involves binding to the Rho guanine nucleotide exchange factor (GEF) ARHGEF28 (p190RhoGEF or Rgnef), and a FAK-ARHGEF28 signaling complex promotes local invasion of orthotopic colon carcinomas in mice 47, 48 . FAK-ARHGEF28 dimerization and the associated increase in FAK activation is thereby linked to elevated tyrosine phosphorylation of paxillin, an adaptor protein involved in FA maturation 49 .…”

Section: Fak In Tumor Cellsmentioning

confidence: 99%

FAK in cancer: mechanistic findings and clinical applications

2014

Self Cite

View full text Add to dashboard Cite

Preface Focal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase that is over-expressed and activated in several advanced-stage solid cancers. FAK promotes tumor progression and metastasis through effects on cancer cells, as well as stromal cells of the tumor microenvironment. FAK’s kinase-dependent and –independent functions control cell movement, invasion, survival, gene expression, and cancer stem cell self-renewal. Small molecule FAK inhibitors decrease tumor growth and metastasis in several preclinical models and possess initial clinical activity in patients with limited adverse events. We discuss FAK signaling effects on both tumor and stromal cell biology that provide rationale and support for future therapeutic opportunities.

show abstract

Section: Fak In Tumor Cellsmentioning

confidence: 99%

FAK in cancer: mechanistic findings and clinical applications

2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Moreover, emerging evidence supports the importance of Rgnef-FAK interactions in promoting tumor progression [37]. In this review, we will expand upon a novel concept that Rgnef also functions as a scaffold in a GEF-independent manner to enhance FAK activation downstream of integrins [38] and how this may impact tumor biology.…”

Section: Rgnef (P190rhogef/arhgef28) and Fakmentioning

confidence: 99%

RhoGEFs in Cell Motility: Novel Links Between Rgnef and Focal Adhesion Kinase

Miller¹,

Kleinschmidt²,

Schlaepfer³

2014

CMM

View full text Add to dashboard Cite

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.

show abstract

“…30 Furthermore, more recent work has suggested that p190RhoGEF is required for proper FAK localization to peripheral adhesions in mouse embryonic fibroblasts. 31 Thus, it may be interesting to investigate a role for other GEFs in directional EC signaling in response to shear stress in future studies.…”

Section: Polarization Of Rac1 Activitymentioning

confidence: 99%