Filling the GAPs in cell dynamics control: BPGAP1 promotes cortactin translocation to the cell periphery for enhanced cell migration.
Cells undergo dynamic changes in morphology or motility during cellular division and proliferation, differentiation, neuronal pathfinding, wound healing, apoptosis, host defense and organ development. These processes are controlled by signalling events relayed through cascades of protein interactions leading to the establishment and maintenance of cytoskeletal networks of microtubules and actin. Various regulators, including the Rho small GTPases (guanine nucleotide triphosphatases), serve as master switches to fine-tune the amplitude, duration as well as the integration of such circuitry responses. Rho GTPases are activated by guanine nucleotide-exchange factors and inactivated by GAPs (GTPase-activating proteins). Although normally down-regulating signalling pathways by catalysing their GTPase activity, many GAPs exist with various protein modules, the functions of which still largely remain unknown. BPGAP1 is a novel RhoGAP that co-ordinately regulates pseudopodia and cell migration through the interplay of its BNIP-2 and Cdc42GAP homology domains serving as a homophilic/heterophilic interaction device, an enzymic RhoGAP domain that inactivates RhoA and a proline-rich region that binds the Src homology-3 domain of cortactin. Both proteins co-localize to cell periphery and enhance cell migration. As a molecular scaffold in cortical actin assembly and organization, cortactin and its interaction with small GTPases, GAPs and tyrosine kinases seems set to provide further insights to the multiplicity and complexity of cell dynamics control. Elucidating how these processes might be individually or co-ordinately regulated through cortactin remains an exciting future challenge.
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Cell Signaling and Developmental Biology Laboratory, Department of Biological Sciences, The National University of Singapore, 14 Science Drive 4, Singapore 117543, The Republic of Singapore.
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D000595:Amino Acid Sequence; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002465:Cell Movement / Q000502:physiology; D058966:Contactins; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D010446:Peptide Fragments / Q000737:chemistry; D014176:Protein Biosynthesis; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018909:src Homology Domains
C479829:ARHGAP8 protein, human; C119020:BNIP1 protein, human; D015816:Cell Adhesion Molecules, Neuronal; D058966:Contactins; D020690:GTPase-Activating Proteins; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2