All cells are equipped to respond to specific stimuli by carrying out dynamic processes that may reorganize the cytoplasm, remodel the cell surface, translocate the cell or generate mechanical forces inside the cell. Many of these motile functions result from the action of the motor protein myosin-II on the actin cytoskeleton. In smooth muscle and nonmuscle cells isoforms of myosin-II are regulated by phosphorylation of the myosin regulatory light chain (RLC) by the calcium/calmodulin-dependent myosin light chain kinase (MLCK). The research in our laboratory is focused on defining signaling pathways that govern the contractile apparatus in smooth muscle tissues and cells. Excessive contraction of these cells underlies certain types of hypertension, coronary artery disease and asthma. Myosin II phosphorylation by other isoforms of MLCK in skeletal and cardiac muscles potentiates the contractile response and may improve the economy of contraction. Current approaches to elucidating roles of MLCK isoforms involve use of transgenic and knockout mice. MLCK activation is measured in contracting muscle from transgenic mice expressing a FRET-based calmodulin-sensor MLCK; enzyme activation and mechanisms of desensitization are studied by additional measures of calcium concentration, RLC phosphorylation and isometric force. The generation of a conditional MLCK knockout mouse model using Cre-lox technology allows studies of not only the role of MLCK in smooth muscle contraction, but also its role in regulating various aspects of cell motility. Smooth muscle cells undergo phenotypic modulation leading to cell migration and proliferation that contribute to the pathology of such diseases as atherosclerosis, restenosis after coronary angioplasty and pulmonary fibrosis. Elucidation of regulatory pathways involved in processes of cell motility will impact both basic understanding and therapeutic approaches to these and other diseases.
RESEARCH INTERESTS
Smooth, skeletal and cardiac muscle physiology
Regulation of contractile proteins
Non-muscle cell motility
RECENT PUBLICATIONS
Isotani E, Zhi G, Lau KS, Huang J, Mizuno Y, Persechini A, Geguchadze R, Kamm KE, Stull JT, "Real-time evaluation of myosin light chain kinase activation in smooth muscle tissues from a transgenic calmodulin-biosensor mouse." Proc Natl Acad Sci U S A, 101(16):6279-84, April 2004
Geguchadze R, Zhi G, Lau KS, Isotani E, Persechini A, Kamm KE, Stull JT, "Quantitative measurements of Ca2+/calmodulin binding and activation of myosin light chain kinase in cells." FEBS Lett, 557(1-3):121-4, January 2004
Xia D, Stull JT, Kamm KE, "Myosin phosphatase targeting subunit 1 affects cell migration by regulating myosin phosphorylation and actin assembly." Exp Cell Res, 304(2):506-17, April 2005
Zhi G, Ryder JW, Huang J, Ding P, Chen Y, Zhao Y, Kamm KE, Stull JT, "Myosin light chain kinase and myosin phosphorylation effect frequency-dependent potentiation of skeletal muscle contraction." Proc Natl Acad Sci U S A, 102(48):17519-24, November 2005
Ryder, JW, KS Lau, KE Kamm and JT Stull, "Enhanced skeletal muscle contraction with myosin light chain phosphorylation by a calmodulin-sensing kinase" J Biol Chem, 282:20447-54, July 2007
SIGNIFICANT PUBLICATIONS
Kamm KE, Stull JT, "Activation of smooth muscle contraction: relation between myosin phosphorylation and stiffness." Science, 232(4746):80-2, April 1986
Lau KS, Grange RW, Isotani E, Sarelius IH, Kamm KE, Huang PL, Stull JT, "nNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle." Physiol Genomics, 2(1):21-7, January 2000
Zhi G, Ryder JW, Huang J, Ding P, Chen Y, Zhao Y, Kamm KE and Stull JT, "Myosin light chain kinase and myosin phosphorylation effect frequency-dependent potentiation of skeletal muscle contraction" Proc Nat Acad Sci (USA), 102:17519-17524, 2005
Isotani E, Zhi G, Lau KS, Huang J, Mizuno Y, Persechini A, Geguchadze R, Kamm KE, Stull JT., "Real-time evaluation of myosin light chain kinase activation in smooth muscle tissues from a transgenic calmodulin-biosensor mouse" Proc Nat Acad Sci (USA), 101:6279-6284, 2004
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