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Published online 8 September 2003. doi:10.1083/jcb.200212060
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© The Rockefeller University Press, 0021-9525/2003/9/1089 $8.00
The Journal of Cell Biology, Volume 162, Number 6, 1089-1098

Article

 Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1

Victoria C. Foletta1, Mei Ann Lim1, Juliana Soosairajah1, April P. Kelly1, Edouard G. Stanley1, Mark Shannon1, Wei He2, Supratik Das2, Joan Massagué2 and Ora Bernard1

1 The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade Parkville, Victoria 3050, Australia
2 Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Address correspondence to Ora Bernard, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade Parkville, Victoria 3050, Australia. Tel.: 61-3-93452494. Fax: 61-3-93470852. email: bernard{at}wehi.edu.au

Bone morphogenetic proteins (BMPs) regulate multiple cellular processes, including cell differentiation and migration. Their signals are transduced by the kinase receptors BMPR-I and BMPR-II, leading to Smad transcription factor activation via BMPR-I. LIM kinase (LIMK) 1 is a key regulator of actin dynamics as it phosphorylates and inactivates cofilin, an actin depolymerizing factor. During a search for LIMK1-interacting proteins, we isolated clones encompassing the tail region of BMPR-II. Although the BMPR-II tail is not involved in BMP signaling via Smad proteins, mutations truncating this domain are present in patients with primary pulmonary hypertension (PPH). Further analysis revealed that the interaction between LIMK1 and BMPR-II inhibited LIMK1's ability to phosphorylate cofilin, which could then be alleviated by addition of BMP4. A BMPR-II mutant containing the smallest COOH-terminal truncation described in PPH failed to bind or inhibit LIMK1. This study identifies the first function of the BMPR-II tail domain and suggests that the deregulation of actin dynamics may contribute to the etiology of PPH.

Key Words: LIM kinase 1; BMPR-II; cytoskeleton; F-actin; cofilin

V.C. Foletta and M.A. Lim contributed equally to this work.

V.C. Foletta's present address is Metabolic Research Unit, School of Health Sciences, Deakin University, Geelong Victoria 3217, Australia.

M.A. Lim's present address is Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229.

A.P. Kelly's present address is Division of Cell Biology and Immunology, School of Life Sciences, Dundee DD1 5EH, UK.

E.G. Stanley's present address is Monash Institute for Reproduction and Development, Monash Medical Centre, Victoria 3168, Australia.

M. Shannon's present address is Peter MacCallum Cancer Institute, Victoria 3002, Australia.

S. Das's present address is Department of Physiology, University of Connecticut Health Center, Farmington, CT 06030.

Abbreviations used in this paper: BMP, bone morphogenetic protein; BMPR, BMP receptor; LAP, LIMK1-associated protein; LIMK, LIM kinase; PAK, p21-activated kinase; PPH, primary pulmonary hypertension; ROCK, Rho-associated kinase.


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