Pathway Map Details

Development_TGF-beta receptor signaling

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p300, MSK1, SOS, NF-kB, TGF-beta receptor type I, SMAD7, p15, Elk-1, TGF-beta 1, SMAD4, Caveolin-1, ErbB2, IKK-beta, TSC-22, TIEG1, FKBP12, SMURF2, APC/hCDH1 complex, FAST-1/2, IKK-alpha, ERK1/2, SMAD3, TAK1(MAP3K7), PAI1, ER81, MEKK4(MAP3K4), NFKBIA, GADD45 beta, H-Ras, Anaphase-promoting complex (APC), c-Raf-1, XIAP, TGF-beta receptor type II, SMURF1, CBP, p21, MEK6(MAP2K6), Sno-N, MEK2(MAP2K2), YY1, MEK3(MAP2K3), SARA, SP1, Shc, Importin (karyopherin)-beta, SMAD2, TAB1, Ski, p38 MAPK, MEK1(MAP2K1)


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 SMAD s 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 [4], [3]. 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]. SMAD s 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 [8], [4]. 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 [4], [2]. 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].

SMAD s 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 [23], [13]. 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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