TGF-beta Receptor type 1 in complex with SB431542
[TGFR1_HUMAN] Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 1A (LDS1A) [MIM:609192]; also known as Furlong syndrome or Loeys-Dietz aortic aneurysm syndrome (LDAS). LDS1 is an aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by arterial tortuosity and aneurysms, craniosynostosis, hypertelorism, and bifid uvula or cleft palate. Other findings include exotropy, micrognathia and retrognathia, structural brain abnormalities, intellectual deficit, congenital heart disease, translucent skin, joint hyperlaxity and aneurysm with dissection throughout the arterial tree.     Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 2A (LDS2A) [MIM:608967]. An aortic aneurysm syndrome with widespread systemic involvement. Physical findings include prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, diffuse arterial aneurysms and dissections, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. LDS2 is characterized by the absence of craniofacial abnormalities with the exception of bifid uvula that can be present in some patients. Note=TGFBR1 mutation Gln-487 has been reported to be associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:16791849). This phenotype, also known as thoracic aortic aneurysms type 5 (AAT5), is distinguised from LDS2A by having aneurysms restricted to thoracic aorta. It is unclear, however, if this condition is fulfilled in individuals bearing Gln-487 mutation, that is why they are considered as LDS2A by the OMIM resource. Defects in TGFBR1 are the cause of multiple self-healing squamous epithelioma (MSSE) [MIM:132800]. A disorder characterized by multiple skin tumors that undergo spontaneous regression. Tumors appear most often on sun-exposed regions, are locally invasive, and undergo spontaneous resolution over a period of months leaving pitted scars.
[TGFR1_HUMAN] Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.      
Publication Abstract from PubMed
Transforming growth factor-beta (TGFbeta) receptor kinase inhibitors have a great therapeutic potential. SB431542 is one of the mainly used kinase inhibitors of the TGFbeta/Activin pathway receptors, but needs improvement of its EC(50) (EC(50)=1 muM) to be translated to clinical use. A key feature of SB431542 is that it specifically targets receptors from the TGFbeta/Activin pathway but not the closely related receptors from the bone morphogenic proteins (BMP) pathway. To understand the mechanisms of this selectivity, we solved the crystal structure of the TGFbeta type I receptor (TbetaRI) kinase domain in complex with SB431542. We mutated TbetaRI residues coordinating SB431542 to their counterparts in activin-receptor like kinase 2 (ALK2), a BMP receptor kinase, and tested the kinase activity of mutated TbetaRI. We discovered that a Ser280Thr mutation yielded a TbetaRI variant that was resistant to SB431542 inhibition. Furthermore, the corresponding Thr283Ser mutation in ALK2 yielded a BMP receptor sensitive to SB431542. This demonstrated that Ser280 is the key determinant of selectivity for SB431542. This work provides a framework for optimising the SB431542 scaffold to more potent and selective inhibitors of the TGFbeta/Activin pathway.
Structural basis for specificity of TGFbeta family receptor small molecule inhibitors.,Ogunjimi AA, Zeqiraj E, Ceccarelli DF, Sicheri F, Wrana JL, David L Cell Signal. 2012 Feb;24(2):476-83. Epub 2011 Oct 1. PMID:21983015
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.