TGFβ (transforming growth factor β) receptor type III directs clathrin-mediated endocytosis of TGFβ receptor types I and II

نویسندگان

  • Sarah MCLEAN
  • Gianni M. DI GUGLIELMO
چکیده

The TGFβ (transforming growth factor β) pathway is an essential cell signalling pathway that is implicated in both normal developmental processes, such as organogenesis, and pathological disorders, such as cancer and fibrosis. There are three prototypical TβRs (TGFβ receptors): TβRI (TβR type I), TGβRII (TβR type II) and TGFβRIII (TβR type III, also known as betaglycan). Whereas the role of TβRII and TβRI in TGFβ signal propagation has been established, the contribution of TβRIII to TGFβ signalling is less well understood. At the cell surface, TβRI and TβRII receptors can be internalized by clathrin-mediated endocytosis and clathrin-independent membrane-raft-dependent endocytosis. Interestingly, the endocytic route of the receptors plays a direct role in TGFβ-dependent Smad signal transduction; receptors endocytosed via clathrin-mediated endocytosis activate Smad signalling, whereas receptors endocytosed via membrane rafts are targeted for degradation. The objective of the present study was to evaluate the contribution of TβRIII to TβRII and TβRI membrane partitioning, receptor half-life and signalling. Using sucrose-density ultracentrifugation to isolate membraneraft fractions, we show that TβRIII recruits both TβRII and TβRI to non-raft membrane fractions. Immunofluorescence microscopy analysis demonstrated that overexpression of TβRIII affects intracellular trafficking of TβRII by recruiting TβRII to EEA1 (early endosome antigen 1)and Rab5-positive early endosomes. Using I-labelled TGFβ1 to follow cell-surface receptor degradation we show that overexpression of TβRIII also extends the receptor half-life of the TβRII–TβRI complex. Interestingly, we also show, using a luciferase reporter assay, that TβRIII increases basal TGFβ signalling. As numerous pathologies show aberrant activation of TGFβ signalling, the present study illustrates that TβRIII may represent a novel therapeutic target.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Recombinant Expression of the Non-glycosylated Extracellular Domain of Human Transforming Growth Factorβ Type II Receptor Using the Baculovirus Expression System in Sf21 Insect Cells

Transforming growth factor beta (TGFβ1, β2, and β3) are 25 kDa disulfide-linked homodimers that regulate many aspects of cellular functions, consist of proliferation, differentiation, adhesion and extracellular matrix formation. TGFβs mediate their biological activities by binding of growth factor ligand to two related, functionally distinct, single-pass transmembrane receptor kinases, known as...

متن کامل

Together and apart: inhibition of DNA synthesis by connexin-43 and its relationship to transforming growth factor β

The membrane and channel protein connexin-43 (Cx43), as well as the cytokine transforming growth factor (TGF) β, suppress proliferative growth in cardiomyocytes and other cell types. Previously we showed that the inhibitory effect of Cx43 is canceled when Cx43 becomes phosphorylated at serine (S) 262 in response to mitogen stimulation. We have now asked if the TGFβ-triggered inhibition of DNA s...

متن کامل

Endocytic deficiency induced by ITSN-1s knockdown alters the Smad2/3-Erk1/2 signaling balance downstream of Alk5

Recently, we demonstrated in cultured endothelial cells and in vivo that deficiency of an isoform of intersectin-1, ITSN-1s, impairs caveolae and clathrin-mediated endocytosis and functionally upregulates compensatory pathways and their morphological carriers (i.e. enlarged endocytic structures, membranous rings or tubules) that are normally underrepresented. We now show that these endocytic st...

متن کامل

TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer

Transforming growth factor β (TGFβ) is a pluripotent cytokine promoting epithelial cell plasticity during morphogenesis and tumour progression. TGFβ binding to type II and type I serine/threonine kinase receptors (TβRII and TβRI) causes activation of different intracellular signaling pathways. TβRI is associated with the ubiquitin ligase tumor necrosis factor receptor (TNFR)-associated factor 6...

متن کامل

Transforming growth factor β and its role in heart disease

Myocardial infarction (MI) is a major form of heart disease that leads to immediate cardiomyocyte death due to ischemia and eventually fibrosis and scar formation and further dysfunction of myocardium and heart failure. Extracellular matrix (ECM) production and tissue repair is conducted by myofibroblasts, which are formed from the normal quiescent cardiac fibroblasts following transformational...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره   شماره 

صفحات  -

تاریخ انتشار 2010