TGF beta signaling pathway
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2008-06-08T18:35:19Z
Gnfnrf
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clean up, typos fixed: asymetrically → asymmetrically, demonstated → demonstrated using [[Project:AutoWikiBrowser|AWB]]
The '''Transforming growth factor beta (TGFβ) signaling pathway''' is involved in many cellular processes in both the adult organism and the developing [[embryo]] including [[cell growth]], [[cell differentiation]], [[apoptosis]], cellular homeostasis and other cellular functions. In spite of the wide range of cellular processes that the TGFβ signaling pathway regulates, the process is relatively simple. TGFβ superfamily ligands bind to a type II receptor, which recruits and [[phosphorylation|phosphorylates]] a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs ([[R-SMAD]]s) which can now bind the coSMAD [[SMAD4]]. R-SMAD/coSMAD complexes accumulate in the nucleus where they act as [[transcription factor]]s and participate in the regulation of target gene expression.
==Mechanism==
===Ligand Binding===
[[Image:TGFbeta Pathway 1.svg|right|150px|TGF Beta ligand binds to receptor]]
The TGF Beta superfamily of ligands include: [[Bone morphogenetic proteins|Bone morphogenetic proteins (BMPs)]], [[Growth and differentiation factor|Growth and differentiation factors (GDFs)]], [[Anti-müllerian hormone|Anti-müllerian hormone (AMH)]], [[Activin]], [[Nodal (protein)|Nodal]] and [[TGF beta|TGFβ]]'s<ref name ="superfam">{{cite web|url=http://www.expasy.org/cgi-bin/nicedoc.pl?PS00250 |title=Prosite Documentation PDOC00223 |accessdate=2006-07-01 |accessmonthday= |accessyear= |author= |last= |first= |authorlink= |coauthors= |date= |year= |month= |format= |work= |publisher= |pages= |language= |archiveurl= |archivedate=}} </ref>. Signaling begins with the binding of a TGF beta superfamily ligand to a TGF beta type II receptor. The type II receptor is a serine/threonine receptor kinase, which [[catalyst|catalyses]] the [[phosphorylation]] of the Type I receptor. Each class of ligand binds to a specific type II receptor<ref name="molbiocell"> {{cite book
| last =Alberts
| first = Bruce
| authorlink =
| coauthors = Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter
| year =2002
| title = Molecular Biology of the Cell
| publisher = Garland Science
| location = New York, NY
| id = ISBN 0-8153-3218-1
}}</ref>.In mammals there are seven known type II receptors and five type I receptors<ref name="Nodal_ALK7">{{cite journal
| last = Munir
| first = S.
| authorlink =
| coauthors = Xu G,Wu Y, Yang B, Lala PK, Peng C.
| year = 2004
| month =Jul
| title = '''Nodal and ALK7 Inhibit Proliferation and Induce Apoptosis in Human Trophoblast Cells'''
| journal = J Biol Chem.
| volume = 279
| issue =
| page =
| pages =
| article =
| doi =
| id =
| url =http://www.jbc.org/cgi/content/full/279/30/31277
| format =
| accessdate = 2006-07-02
}}</ref>.
There are three activins: [[Activin A]], [[Activin B]] and [[Activin AB]]. Activins are involved in embryogenesis and osteogenesis. They also regulate many [[hormones]] including [[pituitary]], gonadal and [[hypothalamic]] hormones as well as [[insulin]]. They are also [[nerve cell]] survival factors.
The BMPs bind to the [[BMPR2|Bone morphogenetic protein receptor type-2]] (BMPR2). They are involved in a multitude of cellular functions including osteogenesis, [[cell differentiation]], anterior/posterior axis specification, growth, and homeostasis.
The TGF beta family include: [[TGFβ1]], [[TGFβ2]], [[TGFβ3]]. Like the BMPS, TGF betas are involved in embryogenesis and cell differentiation, but they are also involved in apoptosis, as well as other functions. They bind to [[TGF-beta receptor type-2]] (TGFBR2).
[[Nodal (protein)|Nodal]] binds to activin A receptor, type IIB [[ACVR2B]]. It can then either form a receptor complex with activin A receptor, type IB ([[ACVR1B]]) or with activin A receptor, type IC ([[ACVR1C]])<ref name="Nodal_ALK7"/>.
===Receptor recruitment and phosphorylation===
[[Image:TGF beta pathway 2.svg|left|150px|Type II receptor recruits type I receptor and phosphorylates]]
The TGF beta ligand binds to a type II receptor dimer, which recruits a type I receptor dimer forming a hetero-tetrameric complex with the ligand<ref name="dimer">{{cite journal
| last =Wrana
| first = JL
| authorlink =
| coauthors = Attisano L, Carcamo J, Zentella A, Doody J, Laiho M, Wang XF, Massague J.
| year = 1992
| month = Dec
| title = '''TGF beta signals through a heteromeric protein kinase receptor complex. '''
| journal = Cell
| volume = 71
| issue =
| page =
| pages =
| article =
| doi =
| id = {{Entrez Pubmed|1333888}}
| url =
| format =
| accessdate =
}} </ref>. These receptors are [[Protein kinase#Serine/threonine-specific protein kinases|serine/threonine kinase receptors]]. They have a [[cysteine]] rich [[Transmembrane receptor#extracellular domain|extracellular domain]], a [[Transmembrane receptor#transmembrane domain|transmembrane domain]] and a [[Transmembrane receptor#cytoplasmic domain|cytoplasmic]] serine/threonine rich domain. The [[GS domain]] of the type I receptor consists of a series of about thirty [[serine]]-[[glycine]] repeats<ref name="GS_domain">{{cite web|url=http://www.sanger.ac.uk/cgi-bin/Pfam/getacc?PF08515 |title=Pfam entry TGF_beta_GS |accessdate=2006-07-01 |accessmonthday= |accessyear= |author= |last= |first= |authorlink= |coauthors= |date= |year= |month= |format= |work= |publisher= |pages= |language= |archiveurl= |archivedate=}}</ref>. The binding of a TGF beta family ligand causes the rotation of the receptors so that their cytoplasmic kinase domains are arranged in a catalytically favorable orientation. The Type II receptor [[phosphorylation|phosphorylates]] [[serine]] residues of the Type I receptor, which activates the protein.
===SMAD phosphorylation===
[[Image:TGF beta pathway step3.svg|right|150px|Type I receptor phosphorylates R-SMAD]]
There are five receptor regulated SMADs: [[SMAD1]], [[SMAD2]], [[SMAD3]], [[SMAD5]] and [[SMAD9]]. There are essentially two intracellular pathways involving these R-SMADs. TGF beta's, Activins and Nodals are mediated by SMAD2 and SMAD3, while BMPs, GDFs and AMH are mediated by [[SMAD1]], [[SMAD5]] and [[SMAD9]]. The binding of the R-SMAD to the type I receptor is mediated by a zinc double finger FYVE domain containing protein. Two such proteins that mediate the TGF beta pathway include SARA (The SMAD anchor for receptor activation) and HGS (Hepatocyte growth factor-regulated tyrosine kinase substrate).
SARA is present in an early [[endosome]] which, by [[clathrin]]-mediated [[endocytosis]], internalizes the receptor complex<ref "SMADendosome"> {{cite journal
| last =
| first =
| authorlink =
| coauthors =
| year = 2005
| month =Mar
| title = '''The role of internalization in transforming growth factor beta1-induced Smad2 association with Smad anchor for receptor activation (SARA) and Smad2-dependent signaling in human mesangial cells.'''
| journal = J Biol Chem.
| volume = 4
| issue =
| page =
| pages = 280
| article =
| doi =
| id = {{Entrez Pubmed|15613484}}
| url =
| format =
| accessdate =
}} </ref>. [[SMAD anchor for receptor activation|SARA]] recruits an [[R-SMAD]]. SARA permits the binding of the R-SMAD to the L45 region of the Type I receptor<ref>{{cite journal
| last = Moustakas
| first = A.
| authorlink =
| coauthors =
| year = 2002
| month = Sep
| title = '''Smad signalling network.'''
| journal = J Cell Sci.
| volume = 115
| issue =
| page =
| pages =
| article =
| doi =
| id = {{Entrez Pubmed|12154066}}
| url =http://jcs.biologists.org/cgi/content/full/115/17/3355
| format =
| accessdate = 2006-07-01
}}</ref>. SARA orients the R-SMAD such that serine residue on its [[C-terminus]] faces the catalytic region of the Type I receptor. The Type I receptor [[phosphorylation|phosphorylates]] the serine residue of the R-SMAD. Phosphorylation induces a conformational change in the [[MH2 (domain)|MH2 domain]] of the R-SMAD and its subsequent dissociation from the receptor complex and SARA<ref>{{cite journal
| last = Souchelnytskyi
| first = S.
| authorlink =
| coauthors = Ronnstrand, L; Heldin, CH; ten Dijke, P
| year =
| month =
| title = '''Phosphorylation of Smad signaling proteins by receptor serine/threonine kinases'''
| journal = Methods Mol Biol
| volume = 124
| issue =
| page =
| pages =
| article =
| doi =
| id = {{Entrez Pubmed|11100470}}
| url =
| format =
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}} </ref>.
===CoSMAD binding===
[[Image:TGF beta Pathway step4.svg|left|150px|R-SMAD binds coSMAD]]
The phosphorylated RSMAD has a high affinity for a coSMAD (eg. [[SMAD4]]) and forms a complex with one. The phosphate group does not act as a docking site for coSMAD, rather the phosphorylation opens up an amino acid stretch allowing interaction.
===Transcription===
[[Image:Pathwaystep5.svg|right|150px|R-SMAD-coSMAD complex enters nucleus]]
The phosphorylated RSMAD/coSMAD complex enters the nucleus where it binds transcription promoters/cofactors and causes the transcription of DNA.
Bone morphogenetic proteins cause the transcription of [[mRNA]]s involved in [[osteogenesis]], [[neurogenesis]], and [[mesoderm|ventral mesoderm]] specification.
TGF betas cause the transcription of mRNAs involved in [[apoptosis]], [[extracellular matrix]] neogenesis and [[immunosuppression]]. It is also involved in [[G1 phase|G1]] arrest in the [[cell cycle]].
Activin causes the transcription of mRNAs involved in [[gonad]]al growth, embryo differentiation and placenta formation.
Nodal causes the transcription of mRNAs involved in left and right axis specification, and [[mesoderm]] and [[endoderm]] induction.
==Pathway regulation==
The TGF beta signaling pathway is involved in a wide range of cellular process and subsequently is very heavily regulated. There are a variety of mechanisms that the pathway is modulated both positively and negatively: There are agonists for ligands and R-SMADs; there are decoy receptors; and R-SMADs and receptors are ubiquitinated.
===Ligand agonists/antagonists===
Both [[chordin]] and [[noggin (protein)|noggin]] are [[antagonists]] of BMP's. They bind BMP's preventing the binding of the ligand to the receptor. It has been demonstrated that Chordin and Noggin dorsalize [[mesoderm]]. They are both found in the dorsal lip of ''[[Xenopus]]'' and convert otherwise [[Epidermis (skin)|epidermis]] specified tissue into neural tissue (see [[neurulation]]). Noggin plays a key role in cartilage and bone patterning. Mice Noggin-/- have excess cartilage and lacked joint formation<ref name="Control">{{cite journal
| last = Massague
| first = J
| authorlink =
| coauthors = Chen YG.
| year = 2000
| month = Mar
| title = '''Controlling TGF-beta signaling.'''
| journal = Genes Dev.
| volume = 14
| issue =
| page =
| pages =
| article =
| doi =
| id = {{Entrez Pubmed|10733523}}
| url =http://intl.genesdev.org/cgi/content/full/14/6/627#B65
| format =
| accessdate = 2006-07-01
}}</ref>.
Members of the DAN family of proteins also antagonize TGF beta family members. They include [[Cerberus (protein)|Cerberus]], [[DAN (protein)|DAN]], and [[Gremlin (protein)|Gremlin]]. These proteins contain nine conserved [[cysteine]]s which can form disulfide bridges. It is believed that DAN antagonizes [[GDF5]], [[GDF6]] and [[GDF7]].
[[Follistatin]] inhibits Activin, which it binds. It directly affects [[follicle-stimulating hormone]] (FSH) secretion. Follistatin also is implicated in prostate cancers where mutations in its gene may preventing it from acting on activin which has anti-proliferative properties<ref name="Control"/>.
[[Lefty (protein)|Lefty]] is a regulator of TGFβ and is involved in the axis patterning during embryogenesis. It is also a member of the TGF superfamily of proteins. It is asymmetrically expressed in the left side of murine embryos and subsequently plays a role in left-right specification. Lefty acts by preventing the phosphorylation of R-SMADs. It does so through a constitutively active TGFβ type I receptor and through a process downstream of its activation<ref name="Lefty">{{cite journal
| last = Ulloa
| first = Luis
| authorlink =
| coauthors = Siamak Tabibzade
| year = 2001
| month = Jun
| title = '''Lefty inhibits receptor-regulated Smad phosphorylation induced by the activated transforming growth factor-beta receptor'''
| journal = J Biol Chem.
| volume = 276
| issue =
| page =
| pages =
| article =
| doi =
| id =
| url =http://www.jbc.org/cgi/content/full/276/24/21397
| format =
| accessdate =2006-07-02
}}</ref>.
===Receptor regulation===
The Transforming growth factor receptor 3 (TGFBR3) is the most abundant of the TGF-β receptors yet<ref name ="TGFBR3">{{cite journal
| last = Blobe
| first = GC
| authorlink =
| coauthors = Liu X, Fang SJ, How T, Lodish HF.
| year = 2001
| month = Oct
| title = '''A novel mechanism for regulating transforming growth factor beta (TGF-beta) signaling. Functional modulation of type III TGF-beta receptor expression through interaction with the PDZ domain protein, GIPC'''
| journal =J Biol Chem.
| volume = 276
| issue =
| page =
| pages =
| article =
| doi =
| id =
| url =http://www.jbc.org/cgi/content/full/276/43/39608
| format =
| accessdate = 2006-07-02
}}</ref>, it has no known signaling domain<ref name="TGF3_mim">{{cite web|url=http://www.ncbi.nih.gov/entrez/dispomim.cgi?id=600742 |title=TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE III; TGFBR3 |accessdate=2006-07-01 |accessmonthday= |accessyear= |author= |last= |first= |authorlink= |coauthors= |date= |year= |month= |format= |work= |publisher=pubmed |pages= |language= |archiveurl= |archivedate=}}</ref>. It however may serve to enhance the binding of TGF beta ligands to TGF beta type II receptors by binding TGFβ and presenting it to TGFBR2. One of the downstream targets of TGF β signaling, ''GIPC'', binds to its PDZ domain, which prevents its proteosomal degradation, which subsequently increases TGFβ activity. It may also serve as an [[inhibin]] coreceptor to [[ActivinRII]]<ref name="Control"/>.
[[BAMBI|BMP and Activin membrane bound inhibitor]] (BAMBI), has a similar extracellular domain as type I receptors. It lacks an intracellular serine/threonine protein kinase domain and hence is a pseudoreceptor. It binds to the type I receptor preventing it from being activated. It serves as a negative regulator of TGF beta signaling and may limit tgf-beta expression during embryogeneis. It requires BMP signaling for its expression<ref name="Control">.
FKBP12 binds the GS region of the type I receptor preventing phosphorylation of the receptor by the type II receptors. It is believed that FKBP12 and its homologs help to prevent type I receptor activation in the absence of a ligands, since ligand binding causes its dissociation<ref name="Control">.
===R-SMAD regulation===
====Role of inhibitory SMADs====
There are two other SMADs which complete the SMAD family, the [[I-SMADs|inhibitory SMADs]] ([[I-SMADS]]), [[SMAD6]] and [[SMAD7]]. They play a key role in the regulation of TFG beta signaling and are involved in negative feeback. Like other SMADs they have an MH1 and an MH2 domain. SMAD7 competes with other R-SMADs with the Type I receptor and prevents their phosphorylation<ref name="Control"/><ref name="BMP_ISMAD">{{cite journal
| last = Itoh
| first =F
| authorlink =
| coauthors = Asao H, Sugamura K, Heldin CH, ten Dijke P, Itoh S.
| year = 2001
| month = Aug
| title = '''Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads'''
| journal = EMBO J.
| volume = 20
| issue =
| page =
| pages =
| article =
| doi =
| id =
| url =http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=11483516
| format =
| accessdate = 2006-07-02
}}</ref>. It resides in the nucleus and upon TGF beta receptor activation translocates to the cytoplasm where it binds the type I receptor. [[SMAD6]] binds SMAD4 preventing the binding of other R-SMADs with the coSMAD. The levels of I-SMAD increase with TGF beta signaling suggesting that they are downstream targets of TGF-beta signaling.
====R-SMAD ubiquitination====
The E3 ubiquitin-protein [[ligase]]s [[SMURF1]] and [[SMURF2]] regulate the levels of SMADs. They accept [[ubiquitin]] from a E2 conjugating enzyme where they transfer ubiquitin to the RSMADs which causes their ubiquitination and subsequent [[proteosome|proteosomal]] degradation. SMURF1 binds to [[SMAD1]] and [[SMAD5]] while SMURF2 binds [[SMAD1]], [[SMAD2]], [[SMAD3]], [[SMAD6]] and [[SMAD7]]. It enhances the inhibitory action of SMAD7 while reducing the transcriptional activities of SMAD2.
==Summary table==
{| class="wikitable"
!style="background:Green; color:white"|TGF Beta superfamily ligand !!style="background:#0054A6; color:white"| Type II Receptor !!style="background:#ED1C24; color:white" |Type I receptor !!style="background:#CADB2A; color:white" | [[R-SMAD]]s !!style="background:#F7931D; color:white" | coSMAD !! Ligand inhibitors
|-
! [[Activin A]]
|[[ACVR2A]]
|[[ACVR1B]] (ALK4)
|[[SMAD2]] , [[SMAD3]]
|[[SMAD4]]
|[[Follistatin]]
|-
! [[GDF1]]
|[[ACVR2A]]
|[[ACVR1B]] (ALK4)
|[[SMAD2]] , [[SMAD3]]
|[[SMAD4]]
|
|-
! [[GDF11]]
|[[ACVR2B]]
|[[ACVR1B]] (ALK4)
|[[SMAD2]] , [[SMAD3]]
|[[SMAD4]]
|
|-
![[Bone morphogenetic proteins]]
|[[BMPR2]]
|[[BMPR1A]] (ALK3), [[BMPR1B]] (ALK6)
|[[SMAD1]] [[SMAD5]], [[SMAD9]]
|[[SMAD4]]
|[[Noggin (protein)|Noggin]], [[Chordin]], [[DAN (protein)|DAN]]
|-
![[Nodal (protein)|Nodal]]
|[[ACVR2B]]
|[[ACVR1B]] (ALK4), [[ACVR1C]] (ALK7)
||[[SMAD2]] , [[SMAD3]]
|[[SMAD4]]
|[[Lefty (protein)|Lefty]]
|-
![[Transforming growth factor beta|TGFβs]]
|[[TGFβRII]]
|[[TGFβRI]] (ALK5)
||[[SMAD2]] , [[SMAD3]]
|[[SMAD4]]
|[[LTBP1]], [[THBS1]], [[Decorin]]
|}
==External links==
*[[KEGG PATHWAY Database|Kyoto Encyclopedia of Genes and Genomes]] -[http://www.genome.ad.jp/dbget-bin/show_pathway?hsa04350+7040 TGF beta signaling pathway] map
==References==
{{reflist}}
{{TGF beta signaling}}
{{Signaling proteins}}
[[Category:Cell signaling]]