Development - TGF-beta receptor signaling

TGF-beta receptor signaling

Transforming growth factor beta (TGF-beta) signaling controls diverse cellular processes, including cell proliferation, differentiation, adhesion and migration [1], [2], [3].

TGF-beta 1 initiates signaling by binding to and bringing together type I and type II receptor serine/threonine kinases (TGF-beta receptor type I and II) on the cell surface. This allows TGF-beta receptor type II to phosphorylate the TGF-beta receptor type I kinase domain. TGF-beta receptor type I then propagates the signal through phosphorylation of the SMAD family member (SMAD) proteins [2], [3]. The recognition of SMADs by TGF-beta receptor type I may be facilitated by auxiliary protein Zinc finger FYVE domain containing 9 (SARA) [2]. SMAD2 and SMAD3 proteins form hetero-oligomeric complexes with SMAD4. These SMAD2/SMAD4 and SMAD3/SMAD4 complexes translocate to the nucleus and, depending on the cell type and their interactions with coactivators or corepressors, function as transcriptional modulators [3], [4]. SMAD3 translocation to the nucleus depends on binding of Importin (karyopherin)-beta [5]. Transcription mediated by SMAD2 or SMAD3 is enhanced by CREB binding protein (CBP)/E1A binding protein p300 (p300) [6], [7]. SMADs can bind DNA directly with low affinity and specificity and thus rely on interactions with other DNA-binding proteins to target specific genes for transcriptional regulation, for example Forkhead box H1 (FAST-1/2) [8]. V-ski sarcoma viral oncogene homolog (Ski) and SKI-like oncogene (SnoN) modulate the nuclear activity of SMAD and function as corepressors antagonize TGF-beta signaling [4], [8]. SMAD3-mediated Anaphase-promoting complex with Fizzy/cell division cycle 20 related 1 (APC/hCDH1 complex) activation leads to degradation of SnoN [9]. YY1 transcription factor (YY1) as a SMAD-interacting negatively regulates TGF-beta signaling [10]. TSC22 domain family member 1 (TSC-22) as a SMAD4-interacting positively regulates TGF-beta-dependent erythroid cell differentiation [11].

SMAD7 inhibits TGF-beta receptor type I [3] via competition with SMAD3 or SMAD2 for binding. SMAD7 interaction leads to the ubiquitination and degradation of the receptors with the help SMAD specific E3 ubiquitin protein ligase (SMURF). TGF-beta/SMAD7/SMURF complex is routed via Caveolin-rich membrane structures and internalized via Caveolin-positive vesicles toward the proteasome for degradation. FK506 binding protein 1A 12kDa (FKBP12) inhibits TGF-beta signaling by binding to the unphosphorylated GS regions of TGF-beta receptor type I. This interaction locks the kinase catalytic center of the TGF-beta receptor type I in an unproductive conformation [2], [4]. TGF-beta induces transcription of the human SMAD7 gene through activation of SMAD3 [12], and transcription factor Ets variant gene 1 (ER81) [13]. Kruppel-like factor 10 (TIEG) represses SMAD7 gene [14].

SMADs functionally cooperate with Sp1 transcription factor (SP1) to activate the Cyclin-dependent kinase inhibitor 1A (p21) promoter [15], Cyclin-dependent kinase inhibitor 2B (p15) [16] (cell cycle regulation [17]), Serpin peptidase inhibitor clade E member 1 (PAI1) [18] (regulation of extracellular matrix [17]).

TGF-beta 1 activates p38 MAPK via Mitogen-activated protein kinase kinase kinase 7 interacting protein 1 (TAB1) [19] or SMAD7 [20]/ Mitogen-activated protein kinase kinase kinase 7 (TAK1(MAP3K7))/ Mitogen-activated protein kinase kinase 3 (MEK3(MAP2K3)). TGF-beta 1 activates, via SMAD3 and SMAD4, expression of Growth arrest and DNA-damage-inducible beta (GADD45 beta) that, possibly via Mitogen-activated protein kinase kinase kinase 4 (MEKK4(MAP3K4)) activates Mitogen-activated protein kinase kinase 6 (MEK6(MAP2K6)) and then p38 MAPK [21]. TGF-beta activates, in p38 MAPK-dependent manner, Antigen identified by monoclonal antibody AJ9 (MSK1) activation [22], which is known to phosphorylate TGF-inducible ER81 [13], [23]. ER81 controls SMAD7 expression and V-erb-b2 erythroblastic leukemia viral oncogene homolog 2 neuro/glioblastoma derived oncogene homolog (ErbB2), which is also involved in SMAD7 expression regulation [13].

TGF-beta receptor directly bind SHC transforming protein 1 (Shc) and via possibly V-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras)/ V-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2) activates Mitogen-activated protein kinase 3 and 1 (ERK1/2). This can lead for example to epithelial-to-mesenchymal transition [24], [25], [26]. ERK activates ELK1 member of ETS oncogene family (Elk-1). Elk-1 transcriptionally activates p15 expression [27].

TGF-beta 1 via TAK1(MAP3K7)/ Nuclear factor NFkappaB inhibitor kinases (IKK) inhibition of Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (NFKBIA) activate Nuclear factor kappa B (NF-kB). As a result of NF-kB activation, NFKBIA mRNA and protein levels are increased leading to post-repression of NF-kB and induction of cell death [28]. TSC-22 stimulates apoptosis too [29], [30].

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