Naccache, S. N., T. Hasson, and A. Horowitz. Binding of Internalized Receptors to the PDZ domain of GIPC/synectin recruits myosin VI to endocytic vesicles. PNAS, 103: 12735–12740, 2006, PubMed ID: 16908842; PubMed Central ID: PMC1568917
We show that a PDZ adaptor protein (GIPC/Synectin) is required for the internalization of cell surface receptors, and couples vesicles to the molecular motor Myosin 6. We report a novel molecular mechanism where the binding of Myo6 to the C-terminus of Synectin potentiates binding of the PDZ domain of synectin to its ligands. Mice devoid of synectin suffer from proteinuria because of the mistargeting of the lipoprotein receptor megalin.
Salikhova, A., L. Wang, A. A. Lanahan, M. Simons, D. Mukhopadhyay, and A. Horowitz. Vascular Endothelial Growth Factor and Semaphorin Induce Neuropilin‐1 Endocytosis via Separate Pathways. Circ. Res., 103: e71-e79, 2008, PubMed ID: 18723443; PubMed Central ID: PMC2674948.
We show that the vascular endothelial growth factor (VEGF) and semaphorin coreceptor Neuropiin-1, which transmits either chemoattractant or repulsive signals, respectively, undergoes clathrin-dependent endocytosis in response to VEGF, and lipid raft-dependent endocytosis in response to semaphorin 3A. This is the first known instance where the ligand determines the endocytic pathway of a cell-surface receptor.
Garnaas, M. K., M. Liu, K. Li, J. Baraban, A. Horowitz*, and R. Ramchandran*. Syx, a novel RhoA guanine exchange factor, is essential for angiogenesis in vivo. (* - co senior author). Circ. Res., 103: 710-716, 2008, PubMed ID: 18757825; PubMed Central ID: PMC2758496.
We established the in vivo function of the RhoA-specific guanine exchange factor (GEF) Syx in the mouse and zebrafish by using a mouse loss-of-function model, and zebrafish knockdown. The defects in these organisms phenocopied each other: major blood vessels generated by vasculogenesis developed normally, but angiogenesis was reduced substantially. We uncovered a potential mechanism of endothelial sprout guidance in which angiomotin, a component of endothelial cell junctions, plays an additive role with Syx in navigating endothelial sprouts.
Wu, C., S. Agrawal, A. Vasanji, S. Sarkaria, J. Xie, B. M. Liu, Anand-Apte, and A. Horowitz. Rab13-dependent trafficking of RhoA is required for directional migration and angiogenesis. J. Biol. Chem., 286: 23511–23520, 2011, PubMed ID: 21543326; PubMed Central ID: PMC3123114.
Accepted without revision. We report that a protein complex that regulates cell junctions is required also for VEGF-driven directional migration and for angiogenesis in vivo. The complex consists of RhoA and Syx, a RhoA guanine exchange factor cross-linked by the Crumbs polarity protein Mupp1 to angiomotin, a phosphatidylinositol binding protein. The Syx-associated complex translocates to the leading edge of migrating cells by membrane trafficking that requires the tight junction recycling GTPase Rab13. Rab13 knockdown in zebrafish impeded sprouting of intersegmental vessels and diminished the directionality of their tip cells.
Ngok, S., R. Geyer, S. Agrawal, A. Kourtidis, L. J. Lewis-Tuffin, K. L. Moodie3, D Huveldt, C. Wu, M. Liu, R. Marx, J. M. Baraban, P. Storz, A. Horowitz*, and P. Z. Anastasiadis*. VEGF and Angiopoietin-1 exert opposing effects on cell junctions by regulating the Rho GEF Syx. J. Cell Biol., 199:1103-1115, 2012 (* - co senior authors). Discussed by the JCB editors in “In this Issue” and in Sci. Signal. editorial (Converging on Syx, Vol. 6, Issue 257, p. ec9); recommended by Faculty of 1000 (http://f1000.com/prime/717978940), PubMed ID: 23253477; PubMed Central ID: PMC3529520.
We report a new molecular mechanism that may account in part for the opposite effects of VEGF and Angiopoietin-1 on vascular permeability. VEGF triggers endothelial cell junction disassembly, whereas Ang1 stabilizes them. We found that the key to these effects is the location of the RhoA-specific GEF Syx: in quiescent or Ang1-treated cells, Syx is anchored to a junctional protein complex where it stabilizes the actin fibers that confer junctions’ structural stability. VEGF translocates Syx to the cell cortex, initiating actin fiber disassembly.
Yang, J., C. Wu, I. Stefanescu, L. Jakobsson, Inna Cheveroneva, and A. Horowitz. RhoA Regulates Neural Differentiation in Murine Stem Cells via Bimodal Signaling. Sci. Signaling. In press, July 2016.
We found that disruption of Syx, a gene coding for a RhoA-specific guanine exchange factor, accelerated retinoic acid–induced neural differentiation in murine embryonic stem cells. We report a new mechanism to explain how RhoA suppresses neural differentiation. RhoA employs two modes of inhibition. In one mode it reduces the expression of Noggin, whereas in the other it generates peripheral actin stress fibers that physically block the exocytosis of Noggin-carrying vesicles.
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