The type II TGF-β receptor phosphorylates Tyr 182 in the type I receptor to activate downstream Src signaling

• Transforming growth factor–β (TGF-β) signaling has important roles during embryonic development and in tissue homeostasis. TGF-β ligands exert cellular effects by binding to type I (TβRI) and type II (TβRII) receptors and induce both SMAD-dependent as well as SMAD-independent intracellular signaling pathways. Activation of the tyrosine kinase Src is one such SMAD-independent consequence of TGF-β signaling. We investigated the mechanism by which TGF-β stimulation activates Src in human and mouse cells. Before TGF-β stimulation, inactive Src was present in a complex with TβRII. Upon TGF-β1 stimulation, which induces the formation of a complex of TβRI and TβRII, TβRII phosphorylated TβRI on serine and threonine residues, which promotes TβRI kinase activity, and on Tyr182. The SH2 domain of Src bound to phosphporylated Tyr182, leading to activation of Src kinase activity. Interaction of the Src SH3 domain with a proline-rich region in TβRI also contributed to binding. TGF-β1–induced Src activation depended on the kinase activity of TβRII but not on that of TβRI, indicating that binding to TβRI activated Src through a non-enzymatic mechanism. Activated Src then phosphorylated TβRI on several tyrosine residues, which may stabilize Src binding to the receptor. In functional assays, Src activation was required for the TGF-β–induced production of fibronectin and for migration in human breast carcinoma cells and for the induction of α-smooth muscle actin (α-SMA) and actin reorganization in mouse fibroblasts. Thus, TGF-β induces Src activation by stimulating a direct interaction with TβRI that depends on tyrosine phosphorylation of TβRI by TβRII. 

Ämnesord

NATURVETENSKAP  -- Biologi -- Cellbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Cell Biology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

Receptors

Transforming Growth Factor beta

Biology with specialization in Molecular Cell Biology

Biologi med inriktning mot molekylär cellbiologi

Publikations- och innehållstyp

ref (ämneskategori)

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