The pro-apoptotic protein Par-4 facilitates vascular contractility by cytoskeletal targeting of ZIPK.
Par-4 (prostate apoptosis response 4) is a pro-apoptotic protein and tumour suppressor that was originally identified as a gene product up-regulated during apoptosis in prostate cancer cells. Here, we show, for the first time, that Par-4 is expressed and co-localizes with the actin filament bundles in vascular smooth muscle. Furthermore, we demonstrate that targeting of ZIPK to the actin filaments, as observed upon PGF-2alpha stimulation, is inhibited by the presence of a cell permeant Par-4 decoy peptide. The same decoy peptide also significantly inhibits PGF-2alpha induced contractions of smooth muscle tissue. Moreover, knockdown of Par-4 using antisense morpholino nucleotides results in significantly reduced contractility, and myosin light chain and myosin phosphatase target subunit phosphorylation. These results indicate that Par-4 facilitates contraction by targeting ZIPK to the vicinity of its substrates, myosin light chain and MYPT, which are located on the actin filaments. These results identify Par-4 as a novel regulator of myosin light chain phosphorylation in differentiated, contractile vascular smooth muscle.
Vetterkind
Susanne
S
Boston Biomedical Research Institute, Watertown, MA, USA.
Morgan
Kathleen G
KG
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology; D064550:Death-Associated Protein Kinases; D015237:Dinoprost / Q000378:metabolism; D055785:Gene Knockdown Techniques; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D018994:Myosin Light Chains / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D018179:Receptors, Thrombin / Q000235:genetics / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D018994:Myosin Light Chains; D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; D018179:Receptors, Thrombin; D015237:Dinoprost; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D043263:Myosin-Light-Chain Phosphatase; C112908:protease-activated receptor 4