RGD Reference Report - Prostate-apoptosis response-4 phosphorylation in vascular smooth muscle. - Rat Genome Database

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Prostate-apoptosis response-4 phosphorylation in vascular smooth muscle.

Authors: MacDonald, JA  Moffat, LD  Al-Ghabkari, A  Sutherland, C  Walsh, MP 
Citation: MacDonald JA, etal., Arch Biochem Biophys. 2013 Jul 1;535(1):84-90. doi: 10.1016/j.abb.2012.11.009. Epub 2012 Dec 3.
RGD ID: 9835413
Pubmed: PMID:23219599   (View Abstract at PubMed)
DOI: DOI:10.1016/j.abb.2012.11.009   (Journal Full-text)

The protein prostate-apoptosis response (Par)-4 has been implicated in the regulation of smooth muscle contraction, based largely on studies with the A7r5 cell line. A mechanism has been proposed whereby Par-4 binding to MYPT1 (the myosin-targeting subunit of myosin light chain phosphatase, MLCP) blocks access of zipper-interacting protein kinase (ZIPK) to Thr697 and Thr855 of MYPT1, whose phosphorylation is associated with MLCP inhibition. Phosphorylation of Par-4 at Thr155 disrupts its interaction with MYPT1, exposing the sites of phosphorylation in MYPT1 and leading to MLCP inhibition and contraction. We tested this "padlock" hypothesis in a well-characterized vascular smooth muscle system, the rat caudal artery. Par-4 was retained in Triton-skinned tissue, suggesting a tight association with the contractile machinery, and indeed Par-4 co-immunoprecipitated with MYPT1. Treatment of Triton-skinned tissue with the phosphatase inhibitor microcystin (MC) evoked phosphorylation of Par-4 at Thr155, but did not induce its dissociation from the contractile machinery. Furthermore, analysis of the time courses of MC-induced phosphorylation of MYPT1 and Par-4 revealed that MYPT1 phosphorylation at Thr697 or Thr855 preceded Par-4 phosphorylation. Par-4 phosphorylation was inhibited by the non-selective kinase inhibitor staurosporine, but not by inhibitors of ZIPK, Rho-associated kinase or protein kinase C. In addition, Par-4 phosphorylation did not occur upon addition of constitutively-active ZIPK to skinned tissue. We conclude that phosphorylation of Par-4 does not regulate contraction of this vascular smooth muscle tissue by inducing dissociation of Par-4 from MYPT1 to allow phosphorylation of MYPT1 and inhibition of MLCP.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of phosphoprotein phosphatase activity  IMP 9835413 RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein binding  IPIPpp1r12a (Rattus norvegicus)9835413 RGD 
protein binding  IPIPawr (Rattus norvegicus)9835413 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pawr  (pro-apoptotic WT1 regulator)
Ppp1r12a  (protein phosphatase 1, regulatory subunit 12A)


Additional Information