Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1.
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.
Foletta
Victoria C
VC
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade Parkville, Victoria 3050, Australia.
Lim
Mei Ann
MA
Soosairajah
Juliana
J
Kelly
April P
AP
Stanley
Edouard G
EG
Shannon
Mark
M
He
Wei
W
Das
Supratik
S
Massague
Joan
J
Bernard
Ora
O
Soosairaiah
Juliana
J
D000818:Animals; D015415:Biomarkers; D055415:Bone Morphogenetic Protein 4; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D019556:COS Cells; D003599:Cytoskeleton / Q000201:enzymology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005057:Eukaryotic Cells / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000503:physiopathology; D054461:Lim Kinases; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011651:Pulmonary Artery / Q000201:enzymology / Q000503:physiopathology; D015398:Signal Transduction / Q000235:genetics*; D051785:Smad Proteins; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
C525809:BMP4 protein, human; D015415:Biomarkers; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D051785:Smad Proteins; D015534:Trans-Activators; D011494:Protein Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases; D017346:Protein Serine-Threonine Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II