title: ADAM12 localizes with c-Src to actin-rich structures at the cell periphery and regulates Src kinase activity.
abstract: ADAM12 is an active metalloprotease playing an important role in tumour progression. Human ADAM12 exists in two splice variants: a long transmembrane form, ADAM12-L, and a secreted form, ADAM12-S. The subcellular localization of ADAM12-L is tightly regulated and involves intracellular interaction partners and signalling proteins. We demonstrate here a c-Src-dependent redistribution of ADAM12-L from perinuclear areas to actin-rich Src-positive structures at the cell periphery, and identified two separate c-Src binding sites in the cytoplasmic tail of ADAM12-L that interact with the SH3 domain of c-Src with different binding affinities. The association between ADAM12-L and c-Src is transient, but greatly stabilized when the c-Src kinase activity is disrupted. In agreement with this observation, kinase-active forms of c-Src induce ADAM12-L tyrosine phosphorylation. Interestingly, ADAM12-L was also found to enhance Src kinase activity in response to external signals, such as integrin engagement. Thus, we suggest that activated c-Src binds, phosphorylates, and redistributes ADAM12-L to specific sites at the cell periphery, which may in turn promote signalling mechanisms regulating cellular processes with importance in cancer.
authors.affiliation: Department of Biomedical Sciences and Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Dorte
authors.initials: D
authors.lastname: Stautz
authors.forename: Archana
authors.initials: A
authors.lastname: Sanjay
authors.forename: Matilde Thye
authors.initials: MT
authors.lastname: Hansen
authors.forename: Reidar
authors.initials: R
authors.lastname: Albrechtsen
authors.forename: Ulla M
authors.initials: UM
authors.lastname: Wewer
authors.forename: Marie
authors.initials: M
authors.lastname: Kveiborg
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072199:ADAM12 Protein; D008841:Actin Cytoskeleton / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D001667:Binding, Competitive; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D019096:Vitronectin / Q000378:metabolism; D018909:src Homology Domains / Q000502:physiology; D019061:src-Family Kinases
chemical_list: D039302:Integrin alphaVbeta3; D008565:Membrane Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D019096:Vitronectin; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human