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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ADAM Proteins / genetics
-
ADAM Proteins / metabolism*
-
ADAM12 Protein
-
Actin Cytoskeleton / metabolism*
-
Binding Sites / physiology
-
Binding, Competitive
-
CSK Tyrosine-Protein Kinase
-
Cell Line
-
Cell Membrane / metabolism*
-
Cell Nucleus / metabolism
-
Cytoskeleton / metabolism
-
Epidermal Growth Factor / genetics
-
Epidermal Growth Factor / metabolism
-
Focal Adhesions / metabolism
-
Humans
-
Integrin alphaVbeta3 / genetics
-
Integrin alphaVbeta3 / metabolism
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism*
-
Models, Biological
-
Mutation / physiology
-
Peptide Fragments / metabolism
-
Phosphorylation / physiology
-
Protein Binding / physiology
-
Protein Transport
-
Protein-Tyrosine Kinases / genetics
-
Protein-Tyrosine Kinases / metabolism*
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism*
-
Recombinant Fusion Proteins / genetics
-
Recombinant Fusion Proteins / metabolism
-
Transfection
-
Vitronectin / metabolism
-
src Homology Domains / physiology
-
src-Family Kinases
Substances
-
Integrin alphaVbeta3
-
Membrane Proteins
-
Peptide Fragments
-
Proto-Oncogene Proteins
-
Recombinant Fusion Proteins
-
Vitronectin
-
Epidermal Growth Factor
-
Protein-Tyrosine Kinases
-
CSK Tyrosine-Protein Kinase
-
src-Family Kinases
-
CSK protein, human
-
ADAM Proteins
-
ADAM12 Protein
-
ADAM12 protein, human