SPSB1, a Novel Negative Regulator of the Transforming Growth Factor-β Signaling Pathway Targeting the Type II Receptor

ABSTRACT Myostatin, a transforming growth factor β (TGF-β) family member, is a potent negative regulator of skeletal muscle growth. In this study we characterized the myostatin signal transduction pathway and examined its effect on bone morphogenetic protein (BMP)-induced adipogenesis. While both BMP7 and BMP2 activated transcription from the BMP-responsive I-BRE-Lux reporter and induced adipogenic differentiation, myostatin inhibited BMP7- but not BMP2-mediated responses. To dissect the molecular mechanism of this antagonism, we characterized the myostatin signal transduction pathway. We showed that myostatin binds the type II Ser/Thr kinase receptor. ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (TβRI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-β-like signaling pathway. We demonstrated that myostatin prevents BMP7 but not BMP2 binding to its receptors and that BMP7-induced heteromeric receptor complex formation is blocked by competition for the common type II receptor, ActRIIB. Thus, our results reveal a strikingly specific antagonism of BMP7-mediated processes by myostatin and suggest that myostatin is an important regulator of adipogenesis.

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Role of transforming growth factor-β in hematologic malignancies

Blood ◽

10.1182/blood-2005-10-4169 ◽

2006 ◽

Vol 107 (12) ◽

pp. 4589-4596 ◽

Cited By ~ 154

Author(s):

Mei Dong ◽

Gerard C. Blobe

Keyword(s):

Growth Factor ◽

Signaling Pathway ◽

Transforming Growth Factor ◽

Myeloproliferative Disorders ◽

Transforming Growth Factor Β ◽

Hematologic Malignancies ◽

Negative Regulator ◽

Cellular Processes ◽

Signaling Field

AbstractThe transforming growth factor-β (TGF-β) signaling pathway is an essential regulator of cellular processes, including proliferation, differentiation, migration, and cell survival. During hematopoiesis, the TGF-β signaling pathway is a potent negative regulator of proliferation while stimulating differentiation and apoptosis when appropriate. In hematologic malignancies, including leukemias, myeloproliferative disorders, lymphomas, and multiple myeloma, resistance to these homeostatic effects of TGF-β develops. Mechanisms for this resistance include mutation or deletion of members of the TGF-β signaling pathway and disruption of the pathway by oncoproteins. These alterations define a tumor suppressor role for the TGF-β pathway in human hematologic malignancies. On the other hand, elevated levels of TGF-β can promote myelofibrosis and the pathogenesis of some hematologic malignancies through their effects on the stroma and immune system. Advances in the TGF-β signaling field should enable targeting of the TGF-β signaling pathway for the treatment of hematologic malignancies.

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Axin Facilitates Smad3 Activation in the Transforming Growth Factor β Signaling Pathway

Molecular and Cellular Biology ◽

10.1128/mcb.21.15.5132-5141.2001 ◽

2001 ◽

Vol 21 (15) ◽

pp. 5132-5141 ◽

Cited By ~ 100

Author(s):

Masao Furuhashi ◽

Ken Yagi ◽

Hideki Yamamoto ◽

Yoichi Furukawa ◽

Shinji Shimada ◽

...

Keyword(s):

Growth Factor ◽

Signaling Pathway ◽

Transforming Growth Factor ◽

Glycogen Synthase ◽

Transforming Growth Factor Β ◽

Receptor Activation ◽

Negative Regulator ◽

Type I ◽

Ligand Stimulation

ABSTRACT Axin acts as a negative regulator in Wnt signaling through interaction with various molecules involved in this pathway, including β-catenin, adenomatous polyposis coli, and glycogen synthase kinase 3β. We show here that Axin also regulates the effects of Smad3 on the transforming growth factor β (TGF-β) signaling pathway. In the absence of activated TGF-β receptors. Axin physically interacted with Smad3 through its C-terminal region located between the β-catenin binding site and Dishevelled-homologous domain. An Axin homologue, Axil (also called conductin), also interacted with Smad3. In the absence of ligand stimulation, Axin was colocalized with Smad3 in the cytoplasm in vivo. Upon receptor activation, Smad3 was strongly phosphorylated by TGF-β type I receptor (TβR-I) in the presence of Axin, and dissociated from TβR-I and Axin. Moreover, the transcriptional activity of TGF-β was enhanced by Axin and repressed by an Axin mutant which is able to bind to Smad3. Axin may thus function as an adapter of Smad3, facilitating its activation by TGF-β receptors for efficient TGF-β signaling.

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