The Rac GTP Exchange Factor TIAM-1 Acts with CDC-42 and the Guidance Receptor UNC-40/DCC in Neuronal Protrusion and Axon Guidance

Abstract

The mechanisms linking guidance receptors to cytoskeletal dynamics in the growth cone during axon extension remain mysterious. The Rho-family GTPases Rac and CDC-42 are key regulators of growth cone lamellipodia and filopodia formation, yet little is understood about how these molecules interact in growth cone outgrowth or how the activities of these molecules are regulated in distinct contexts. UNC-73/Trio is a well-characterized Rac GTP exchange factor in Caenorhabditis elegans axon pathfinding, yet UNC-73 does not control CED-10/Rac downstream of UNC-6/Netrin in attractive axon guidance. Here we show that C. elegans TIAM-1 is a Rac-specific GEF that links CDC-42 and Rac signaling in lamellipodia and filopodia formation downstream of UNC-40/DCC. We also show that TIAM-1 acts with UNC-40/DCC in axon guidance. Our results indicate that a CDC-42/TIAM-1/Rac GTPase signaling pathway drives lamellipodia and filopodia formation downstream of the UNC-40/DCC guidance receptor, a novel set of interactions between these molecules. Furthermore, we show that TIAM-1 acts with UNC-40/DCC in axon guidance, suggesting that TIAM-1 might regulate growth cone protrusion via Rac GTPases in response to UNC-40/DCC. Our results also suggest that Rac GTPase activity is controlled by different GEFs in distinct axon guidance contexts, explaining how Rac GTPases can specifically control multiple cellular functions.

Mutationally activated Rho GTPases in cancer

“…Recent work from our laboratory further demonstrates the utility of using C. elegans developmental neurobiology as a platform to study oncogenesis, as we have shown that TIAM-1, a Rac GEF, acts downstream of CDC-42 and upstream of the Rac GTPases in a linear pathway that regulates neuronal development and protrusion downstream of the UNC-40/Deleted in colorectal cancer(DCC) receptor molecule. 51 Further work in oncogene and tumor suppressor regulation and function in C. elegans, combined with data from other systems, will continue to reveal new insights into the pathological mechanisms underlying tumor formation, maintenance, and metastasis.…”

Recruitment of β-Catenin to N-Cadherin Is Necessary for Smooth Muscle Contraction

“…E-Cadherin is required for the activation of PI3K in epithelial ovarian cancer cells (36). PI3K is able to activate Tiam-1 and VAV-2 (guanine nucleotide exchange factors), which may subsequently regulate Rac/Cdc42 activation and actin polymerization (33,37). Here the knockdown of ␤-catenin or the disruption of ␤-catenin with N-cadherin did not affect actin polymerization upon contractile activation.…”

“…Therefore, cadherin-regulated actin filament assembly is not mediated by ␤-catenin in smooth muscle during contractile activation. Cadherin may directly interact with pleckstrin homology domains on Tiam-1 or VAV-2, which activates Rac/Cdc42 and actin polymerization (33,37). E-Cadherin is required for the activation of the small GTPase Rho in epithelial cells (38,39).…”

“…Inhibition of actin polymerization by molecular approaches attenuates the intracellular trafficking of GLUT4 during insulin activation (30). In addition, Rac may promote adherens junction assembly by binding to IQ motif containing GTPase activating protein (a scaffold protein), which enhances the linkage of actin filaments to ␤-catenin (33), and by promoting actin polymerization (8,37,39). Furthermore, actin polymerization regulates Raf-1 translocation in smooth muscle cells (20).…”

Control of developmental networks by Rac/Rho small GTPases: How cytoskeletal changes during embryogenesis are orchestrated

“…Both need actin cytoskeleton rearrangements in the growth cone or at the leading edges of the plasma membrane of migrating cells 36, 44, 45. In C. elegans , in response to UNC‐6/Netrin signaling, Rho GTPase CDC‐42 activates the C. elegans GEF TIAM (T‐cell lymphoma Invasion and Metastasis Factor 1), which is a GTP exchange factor specific for Rac and which activates Rac signaling, in lamellipodia and filopodia formation and axon guidance 46, 47. Recently, Zheng et al showed that the Rac GEFs UNC‐73/Trio and TIAM‐1 promote neuronal extension toward opposite directions: UNC‐73/Trio promotes anterior extension whereas TIAM‐1 causes a posterior neurite extension 48.…”