title: Microtubule and Actin Interplay Drive Intracellular c-Src Trafficking.
abstract: The proto-oncogene c-Src is involved in a variety of signaling processes. Therefore, c-Src spatiotemporal localization is critical for interaction with downstream targets. However, the mechanisms regulating this localization have remained elusive. Previous studies have shown that c-Src trafficking is a microtubule-dependent process that facilitates c-Src turnover in neuronal growth cones. As such, microtubule depolymerization lead to the inhibition of c-Src recycling. Alternatively, c-Src trafficking was also shown to be regulated by RhoB-dependent actin polymerization. Our results show that c-Src vesicles primarily exhibit microtubule-dependent trafficking; however, microtubule depolymerization does not inhibit vesicle movement. Instead, vesicular movement becomes both faster and less directional. This movement was associated with actin polymerization directly at c-Src vesicle membranes. Interestingly, it has been shown previously that c-Src delivery is an actin polymerization-dependent process that relies on small GTPase RhoB at c-Src vesicles. In agreement with this finding, microtubule depolymerization induced significant activation of RhoB, together with actin comet tail formation. These effects occurred downstream of GTP-exchange factor, GEF-H1, which was released from depolymerizing MTs. Accordingly, GEF-H1 activity was necessary for actin comet tail formation at the Src vesicles. Our results indicate that regulation of c-Src trafficking requires both microtubules and actin polymerization, and that GEF-H1 coordinates c-Src trafficking, acting as a molecular switch between these two mechanisms.
authors: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors: Christopher
authors: C
authors: Arnette
authors: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors: Keyada
authors: K
authors: Frye
authors: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors: Irina
authors: I
authors: Kaverina
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D002465:Cell Movement; D051356:Cortactin / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D018613:Microscopy, Confocal; D008870:Microtubules / Q000378:metabolism*; D015739:Nocodazole / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D021381:Protein Transport; D000090063:Proto-Oncogene Mas; D051381:Rats; D055213:Retinal Pigment Epithelium / Q000166:cytology; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C577356:ARHGEF2 protein, human; D000199:Actins; C000609216:Arhgef2 protein, rat; D051356:Cortactin; D005353:Fibronectins; C000715470:MAS1 protein, human; D011108:Polymers; D000090063:Proto-Oncogene Mas; D064067:Rho Guanine Nucleotide Exchange Factors; C114864:WASF1 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D049452:Green Fluorescent Proteins; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D020743:rhoB GTP-Binding Protein; D015739:Nocodazole