Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

TGFBR1 (P36897) - Overview - Molecular Target Synopsis

Protein


TGFBR1, TGF-beta receptor type-1
Enzyme Classification 2.7.11.30
UniProt P36897

Also Known as TGFR1_HUMAN, TGFBR1, ALK5, SKR4

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. Homodimer; in the endoplasmic reticulum but also at the cell membrane. Heterohexamer; TGFB1, TGFB2 and TGFB3 homodimeric ligands assemble a functional receptor composed of two TGFBR1 and TGFBR2 heterodimers to form a ligand-receptor heterohexamer. The respective affinity of TGBRB1 and TGFBR2 for the ligands may modulate the kinetics of assembly of the receptor and may explain the different biological activities of TGFB1, TGFB2 and TGFB3. Interacts with CD109; inhibits TGF-beta receptor activation in keratinocytes. Interacts with RBPMS. Interacts (unphosphorylated) with FKBP1A; prevents TGFBR1 phosphorylation by TGFBR2 and stabilizes it in the inactive conformation. Interacts with SMAD2, SMAD3 and ZFYVE9; ZFYVE9 recruits SMAD2 and SMAD3 to the TGF-beta receptor. Interacts with TRAF6 and MAP3K7; induces MAP3K7 activation by TRAF6. Interacts with PARD6A; involved in TGF-beta induced epithelial to mesenchymal transition. Interacts with SMAD7, NEDD4L, SMURF1 and SMURF2; SMAD7 recruits NEDD4L, SMURF1 and SMURF2 to the TGF-beta receptor. Interacts with USP15 and VPS39. Interacts with SDCBP (via C-terminus) (PubMed:25893292) Interacts with CAV1 and this interaction is impaired in the presence of SDCBP (PubMed:25893292). Interacts with APPL1; interaction is TGF beta dependent; mediates trafficking of the TGFBR1 from the endosomes to the nucleus via microtubules in a TRAF6-dependent manner (PubMed:26583432).

5QIM
TGF-BETA RECEPTOR TYPE 1 KINASE DOMAIN (T204D) IN COMPLEX WITH N-{4- [3-(5-METHOXYPYRIDIN-2-YL)-1H-PYRROLO[3,2-B] PYRIDIN-2-YL]PYRIDIN-2- YL}ACETAMIDE
RCSB/PDB
Inspect Structure
See all 3D Structures for TGFBR1

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: TGFBR1 is active in the following subcellular-locations: cell junction, cell membrane, cell surface, membrane raft, tight junction.
GO terms: TGFBR1 is active in the following subcellular-locations: activin receptor complex, bicellular tight junction, cell, cell surface, endosome, integral component of plasma membrane, intracellular membrane-bounded organelle, membrane, membrane raft, nucleus, plasma membrane, receptor complex.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project TGFBR1 has gain in 1 cell-lines, loss in 3 cell-lines and no signal in 1001 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: SK_MEL_28, SF_539, BT_549

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: MS751, HCC1576, Hs 675.T

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: NHLF, HSMM, AG445

(see details)

RNA Interference


TGFBR1 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: MCF12A, SKGT4. (see details)

3D Structures


For TGFBR1 there are:
35 structures (57 chains) solved
26 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


TGFBR1 has been screened with 1201 compounds (2563 bioactivities), 532 compounds have bioactivities that show binding affinity of <= 500nM (853 bioactivities). (see details)