LIM mineralization protein-1 potentiates bone morphogenetic protein responsiveness via a novel interaction with Smurf1 resulting in decreased ubiquitination of Smads.
Development and repair of the skeletal system and other organs is highly dependent on precise regulation of bone morphogenetic proteins (BMPs), their receptors, and their intracellular signaling proteins known as Smads. The use of BMPs clinically to induce bone formation has been limited in part by the requirement of much higher doses of recombinant proteins in primates than were needed in cell culture or rodents. Therefore, control of cellular responsiveness to BMPs is now a critical area that is poorly understood. We determined that LMP-1, a LIM domain protein capable of inducing de novo bone formation, interacts with Smurf1 (Smad ubiquitin regulatory factor 1) and prevents ubiquitination of Smads. In the region of LMP responsible for bone formation, there is a motif that directly interacts with the Smurf1 WW2 domain and can effectively compete with Smad1 and Smad5 for binding. We have shown that small peptides containing this motif can mimic the ability to block Smurf1 from binding Smads. This novel interaction of LMP-1 with the WW2 domain of Smurf1 to block Smad binding results in increased cellular responsiveness to exogenous BMP and demonstrates a novel regulatory mechanism for the BMP signaling pathway.
Sangadala
Sreedhara
S
Atlanta Veterans Affairs Medical Center and the Department of Orthopaedic Surgery, Emory University School of Medicine, Atlanta, Georgia 30329.
Boden
Scott D
SD
Atlanta Veterans Affairs Medical Center and the Department of Orthopaedic Surgery, Emory University School of Medicine, Atlanta, Georgia 30329. Electronic address: Scott_boden@emory.org.
Viggeswarapu
Manjula
M
Atlanta Veterans Affairs Medical Center and the Department of Orthopaedic Surgery, Emory University School of Medicine, Atlanta, Georgia 30329.
Liu
Yunshan
Y
Atlanta Veterans Affairs Medical Center and the Department of Orthopaedic Surgery, Emory University School of Medicine, Atlanta, Georgia 30329.
Titus
Louisa
L
Atlanta Veterans Affairs Medical Center and the Department of Orthopaedic Surgery, Emory University School of Medicine, Atlanta, Georgia 30329.
D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D060588:LIM Domain Proteins; D059630:Mesenchymal Stem Cells / Q000166:cytology; D008969:Molecular Sequence Data; D011485:Protein Binding; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C484380:PDLIM7 protein, human; D051785:Smad Proteins; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases