The LIM protein leupaxin is enriched in smooth muscle and functions as an serum response factor cofactor to induce smooth muscle cell gene transcription.
Leupaxin is a LIM domain-containing adapter protein belonging to the paxillin family that has been previously reported to be preferentially expressed in hematopoietic cells. Herein, we identified leupaxin in a screen for focal adhesion kinase binding partners in aortic smooth muscle, and we show that leupaxin is enriched in human and mouse vascular smooth muscle and that leupaxin expression is dynamically regulated during development. In addition, our studies reveal that leupaxin can undergo cytoplasmic/nuclear shuttling and functions as an serum response factor cofactor in the nucleus. We found that leupaxin forms a complex with serum response factor and associates with CArG-containing regions of smooth muscle promoters and that ectopic expression of leupaxin induces smooth muscle marker gene expression in both 10T1/2 cells and rat aortic smooth muscle cells. Subsequent studies indicated that enhanced focal adhesion kinase activity (induced by fibronectin or expression of constitutively active focal adhesion kinase) attenuates the nuclear accumulation of leupaxin and limits the ability of leupaxin to enhance serum response factor-dependent gene transcription. Thus, these studies indicate that modulation of the subcellular localization of serum response factor cofactors is 1 mechanism by which extracellular matrix-dependent signals may regulate phenotypic switching of smooth muscle cells.
Sundberg-Smith
Liisa J
LJ
Department of Pathology, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
DiMichele
Laura A
LA
Sayers
Rebecca L
RL
Mack
Christopher P
CP
Taylor
Joan M
JM
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D001692:Biological Transport; D015815:Cell Adhesion Molecules / Q000494:pharmacology / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured / Q000187:drug effects; D003331:Coronary Vessels / Q000166:cytology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000502:physiology; D022001:Focal Adhesions / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D009215:Myometrium / Q000166:cytology; D009928:Organ Specificity; D010750:Phosphoproteins / Q000494:pharmacology / Q000502:physiology*; D025941:Protein Interaction Mapping; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D027602:Serum Response Element / Q000187:drug effects / Q000502:physiology*; D026362:Serum Response Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors; D014158:Transcription, Genetic
D015815:Cell Adhesion Molecules; C112251:LPXN protein, human; C504469:Lpxn protein, mouse; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; C476858:SRF protein, human; D026362:Serum Response Factor; D014157:Transcription Factors; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse