Development TGF-beta receptor signaling
TGF-beta receptor signaling
Transforming growth factor beta ( TGF-beta ) signaling controls diversecellular processes, including cell proliferation, differentiation, adhesion and migration[1], [2], [3].
TGF-beta 1 initiates signaling by binding to and bringing together type I andtype 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 theTGF-beta receptor type I kinase domain. TGF-beta receptor type I then propagatesthe signal through phosphorylation of the SMAD family member ( SMAD ) proteins[2], [3]. The recognition of SMAD s by TGF-betareceptor type I may be facilitated by auxiliary protein Zinc finger FYVE domaincontaining 9 ( SARA ) [2]. SMAD2 and SMAD3 proteinsform hetero-oligomeric complexes with SMAD4. These SMAD2/ SMAD4and SMAD3/ SMAD4 complexes translocate to the nucleus and, depending onthe cell type and their interactions with coactivators or corepressors, function astranscriptional modulators [4], [3]. SMAD3 translocationto the nucleus depends on binding of Importin (karyopherin)-beta [5].Transcription mediated by SMAD2 or SMAD3 is enhanced by CREB bindingprotein ( CBP )/E1A binding protein p300 ( p300 ) [6], [7]. SMAD s can bind DNA directly with low affinity and specificity and thusrely on interactions with other DNA-binding proteins to target specific genes fortranscriptional 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 corepressorsantagonize 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 -interactingnegatively regulates TGF-beta signaling [10].
SMAD7 inhibits TGF-beta receptor type I [3] via competitionwith SMAD3 or SMAD2 for binding. SMAD7 interaction leads to theubiquitination and degradation of the receptors with the help SMAD specific E3 ubiquitinprotein ligase ( SMURF ). TGF-beta/ SMAD7/ SMURF complex isrouted 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 GSregions of TGF-beta receptor type I. This interaction locks the kinase catalyticcenter of the TGF-beta receptor type I in an unproductive conformation [4], [2]. TGF-beta induces transcription of the humanSMAD7 gene through activation of SMAD3 [11], and transcriptionfactor Ets variant gene 1 ( ER81 ) [12]. Kruppel-like factor 10 (TIEG ) represses SMAD7 gene [13].
SMAD s functionally cooperate with Sp1 transcription factor ( SP1 ) toactivate the Cyclin-dependent kinase inhibitor 1A ( p21 ) promoter [14], Cyclin-dependent kinase inhibitor 2B ( p15 ) [15] (cellcycle regulation [16]), Serpin peptidase inhibitor clade E member 1 (PAI1 ) [17] (regulation of extracellular matrix [16]).
TGF-beta 1 activates p38 MAPK via Mitogen-activated protein kinasekinase kinase 7 interacting protein 1 ( TAB1 ) [18] or SMAD7[19]/ Mitogen-activated protein kinase kinase kinase 7 ( TAK1(MAP3K7))/ Mitogen-activated protein kinase kinase 3 ( MEK3(MAP2K3) ). TGF-beta 1activates, via SMAD3 and SMAD4, expression of Growth arrest andDNA-damage-inducible beta ( GADD45 beta ) that, possibly via Mitogen-activatedprotein kinase kinase kinase 4 ( MEKK4(MAP3K4) ) activates Mitogen-activatedprotein kinase kinase 6 ( MEK6(MAP2K6) ) and then p38 MAPK [20]. TGF-beta activates, in p38 MAPK -dependent manner, Antigenidentified by monoclonal antibody AJ9 ( MSK1 ) activation [21], whichis known to phosphorylate TGF-inducible ER81 [22], [12].ER81 controls SMAD7 expression and V-erb-b2 erythroblastic leukemia viraloncogene homolog 2 neuro/glioblastoma derived oncogene homolog ( ErbB2 ), which isalso involved in SMAD7 expression regulation [12].
TGF-beta receptor directly bind SHC transforming protein 1 ( Shc ) andvia 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-activatedprotein kinase kinase 1 and 2 ( MEK1 and MEK2 ) activates Mitogen-activatedprotein kinase 3 and 1 ( ERK1/2 ). This can lead for example toepithelial-to-mesenchymal transition [23], [24], [25]. ERK activates ELK1 member of ETS oncogene family ( Elk-1 ).Elk-1 transcriptionally activates p15 expression [26].
TGF-beta 1 via TAK1(MAP3K7)/ Nuclear factor NFkappaB inhibitor kinases( IKK ) inhibition of Nuclear factor of kappa light polypeptide gene enhancer inB-cells inhibitor alpha ( NFKBIA ) activate Nuclear factor kappa B ( NF-kB). As a result of NF-kB activation, NFKBIA mRNA and protein levels areincreased leading to post-repression of NF-kB and induction of cell death [27].
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