Victor W. Hsu, MD
Associate Professor, Department of Medicine, Harvard Medical School
Associate Immunologist, Rheumatology, Immunology and Allergy, Brigham And Women's Hospital
DF/HCC Program AffiliationAngiogenesis, Invasion and Metastasis
A hallmark of malignancy is cell migration that results in tissue infiltration and distant metastasis. Cell migration requires the formation of surface membrane protrusions. This process requires the coordination of intracellular actin rearrangement with membrane transport. Besides the Rho family of small GTPases that are well known to participate in this coordination, the ARF small GTPases have also been discovered to regulate both actin rearrangement and membrane transport. Focusing on how ARFs regulate membrane transport, we have found that their GTPase-activating proteins (GAPs) not only functions as key upstream regulators of the GTPase cycle but also as critical downstream effectors by acting as components of different coat proteins. Recently, we have found that ACAP1, an ARF6 GAP that also functions as an ARF6 effector in cargo sorting at the recycling endosome, is critical for cell migration. This role requires the phosphorylation of ACAP1 by the protein kinase Akt whose contribution to cancer is well appreciated. As tumors are capable of commandeering diverse mechanisms that normally regulate and mediate cell migration to achieve metastasis, we anticipate that a further understanding of how the ARF small GTPases regulate membrane transport will likely provide novel molecular targets for the future design of intervention against tumor migration.
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