SMAD4

SMAD4
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	1DD1, 1G88, 1MR1, 1U7F, 1U7V, 1YGS, 5MEY, 5MEZ, 5MF0
Identifikatori
Aliasi	SMAD4
Vanjski ID-jevi	OMIM: 600993 MGI: 894293 HomoloGene: 31310 GeneCards: SMAD4
Lokacija gena (čovjek)
Hrom.	Hromosom 18 (čovjek)
Kraj	51,085,045 bp
Lokacija gena (miš)
Hrom.	Hromosom 18 (miš)
Kraj	73,836,851 bp
Obrazac RNK ekspresije
	; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• protein homodimerization activity; • protein heterodimerization activity; • RNA polymerase II transcription regulatory region sequence-specific DNA binding; • vezivanje iona metala; • vezivanje sa DNK; • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity; • sequence-specific DNA binding; • GO:0001158 cis-regulatory region sequence-specific DNA binding; • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific; • I-SMAD binding; • collagen binding; • GO:0001948, GO:0016582 vezivanje za proteine; • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding; • R-SMAD binding; • vezivanje identičnih proteina; • sulfate binding; • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific; • GO:0001104 transcription coregulator activity; • molecular function regulator; • chromatin binding;
Ćelijska komponenta	• jedro; • citoplazma; • transcription regulator complex; • activin responsive factor complex; • intracellular anatomical structure; • RNA polymerase II transcription regulator complex; • nukleoplazma; • centrosom; • citosol; • SMAD protein complex;
Biološki proces	• negative regulation of cell population proliferation; • Spermatogeneza; • positive regulation of pathway-restricted SMAD protein phosphorylation; • positive regulation of luteinizing hormone secretion; • regulation of cell population proliferation; • cardiac septum development; • negative regulation of cell death; • regulation of hair follicle development; • cellular response to BMP stimulus; • epithelial to mesenchymal transition involved in endocardial cushion formation; • brainstem development; • Ćelijska proliferacija; • regulation of binding; • SMAD protein complex assembly; • metanephric mesenchyme morphogenesis; • positive regulation of epithelial to mesenchymal transition; • GO:0007329 positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus; • GO:0044324, GO:0003256, GO:1901213, GO:0046019, GO:0046020, GO:1900094, GO:0061216, GO:0060994, GO:1902064, GO:0003258, GO:0072212 regulation of transcription by RNA polymerase II; • branching involved in ureteric bud morphogenesis; • GO:0009373 regulation of transcription, DNA-templated; • embryonic digit morphogenesis; • uterus development; • axon guidance; • somatic stem cell population maintenance; • Gastrulacija; • positive regulation of histone H3-K4 methylation; • GO:0045996 negative regulation of transcription, DNA-templated; • response to transforming growth factor beta; • endothelial cell activation; • positive regulation of transforming growth factor beta receptor signaling pathway; • single fertilization; • transforming growth factor beta receptor signaling pathway; • anterior/posterior pattern specification; • in utero embryonic development; • positive regulation of cell proliferation involved in heart valve morphogenesis; • atrioventricular valve formation; • GO:0007243 intracellular signal transduction; • developmental growth; • endoderm development; • cellular iron ion homeostasis; • Nefrogeneza; • GO:0007364, GO:0007361, GO:0007358 formation of anatomical boundary; • positive regulation of histone H3-K9 acetylation; • regulation of transforming growth factor beta2 production; • interleukin-6-mediated signaling pathway; • GO:1901227 negative regulation of transcription by RNA polymerase II; • male gonad development; • ovarian follicle development; • endocardial cell differentiation; • nephrogenic mesenchyme morphogenesis; • gastrulation with mouth forming second; • female gonad development; • SMAD protein signal transduction; • response to hypoxia; • atrioventricular canal development; • mesoderm development; • negative regulation of cell growth; • GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated; • BMP signaling pathway; • tissue morphogenesis; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • positive regulation of SMAD protein signal transduction; • somite rostral/caudal axis specification; • sebaceous gland development; • positive regulation of follicle-stimulating hormone secretion; • positive regulation of BMP signaling pathway; • neural crest cell differentiation; • seminiferous tubule development; • female gonad morphogenesis; • regulation of transforming growth factor beta receptor signaling pathway; • neuron fate commitment; • transcription, DNA-templated; • outflow tract septum morphogenesis; • left ventricular cardiac muscle tissue morphogenesis; • negative regulation of cardiac muscle hypertrophy; • protein deubiquitination; • ventricular septum morphogenesis; • negative regulation of ERK1 and ERK2 cascade; • negative regulation of cardiac myofibril assembly; • protein homotrimerization; • pri-miRNA transcription by RNA polymerase II; • secondary palate development; • anatomical structure morphogenesis; • Ćelijska diferencijacija; • mesendoderm development;
	Izvori:Amigo / QuickGO
Ortolozi
	4089
	17128
	ENSG00000141646
	ENSMUSG00000024515
	Q13485
	P97471
	NM_005359
	NM_008540; NM_001364967; NM_001364968
	NP_005350
	NP_032566; NP_001351896; NP_001351897
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

SMAD4 ili član 4 porodice SMAD, reaktori majke protiv dekapentaplegijskog homologa 4 ili DPC4 (deletirani-4 u raku gušterače) je visoko konzervirani protein, u svim metazoama. Pripada porodici SMAD proteinskih faktora transkripcije, koji deluju kao posrednici u transmisiji TGF-β signala. Porodica citokina TGFβ regulira kritične procese tokom životnog ciklusa metazoa, sa važnim ulogama tokom razvoja embrion a, homeostaza tkiva, regeneracije i imunske regulacije .^[5]

Dužina polipeptidnog lanca je 552 aminokiseline, sa molekulskom težinom od 60.439.^[6].

SMAD 4 pripada grupi ko-SMAD (koposrednik SMAD), drugoj klasi SMAD porodice. SMAD4 je jedini poznati ko-SMAD u većini metazoa. Također pripada i proteina porodice Darwin, koji moduliraju članove superporodice porodica TGFβ, porodice proteina od kojih svi imaju ulogu u regulaciji ćelijskih odgovora. SMAD4 sisara je homolog proteina rakcije majke protiv dekapentaplegika kod Drosophila, zvanih Medeja.^[7]

SMAD4 stupa u interakciju s R-Smad-ima, kao što su SMAD2, SMAD3, SMAD1, SMAD5 i SMAD8 (također zvani SMAD9), da bi formirao heterotrimerne komplekse. U jedru, kompleks SMAD4 i dva R-SMADS vežu se za DNK i reguliraju ekspresiju različitih gena, ovisno o ćelijskom kontekstu.^[7] Unutarćelijske reakcije koje uključuju SMAD4, na površini ćelija pokreću vezanje faktora rasta iz porodice TGFβ. Sekvenca unutarćelijskih reakcija koja uključuje SMAD naziva se SMAD-ni put ili put transformirajućeg faktora rasta beta (TGF-β), jer sekvenca započinje ćelijskim prepoznavanjem TGF-β.

Gen

Kod sisara SMAD4 kodiran je genom koji se nalazi na hromosomu 18. Kod ljudi, gen SMAD4 sadrži 54-829 baznih parova i nalazi se od para br. 51,030.212 do para 51,085.041, u regiji q21,1 hromosoma 18.^[8]^[9]

Hromosom 18 kod *Homo sapiens*. Gen *SMAD 4* nalazi se na dugom kraku hromosoma, u lokusu q21.1. Ovo mjesto odgovara crnoj prugi između regija q12.3 i q21.2.

Protein

SMAD4 je 552-aminokiselinski polipeptid molekulske težine 60.439 Da. SMAD4 ima dva funkcionalna domena poznat kao MH1 i MH2.

SMAD 4 sastoji se od tri glavna domena, uključujući MH1 (gore), MH2 (dolje) i povezujući domen (desno).

Kompleks dva SMAD3 (ili dva SMAD2) i jedan SMAD4, direktno se veže za DNK interakcijom njihovih MH1 domena. Ovi kompleksi se upućuju na odgovarajuća mjesta u genomu pomoću transkripcijskih faktora, koji definiraju ćelijskuu lozu (LDTF) određujući kontekst-zavisnu prirodu djelovanja TGF-β. Rani uvidi u specifičnost vezanja DNK za Smad-proteine proizašli su iz pregleda za vezanje oligonukleotida, koji su identificirali palindromski dupleks 5'-GTCTAGAC-3', kao vezujuću sekvencu visokog afiniteta za SMAD3 i SMAD4 MH1 domene.^[10] Ostali motivi su također identificirani u promotorima i pojačivačima. Ova dodatna mjesta sadrže motiv CAGCC i konsenzusne sekvence GGC (GC) | (CG), potonje poznate i kao 5GC mjesta.^[11] Motivi 5GC su visoko predstavljeni kao klasteri lokacija, u SMAD-vezanim regijama širom genoma. Ovi klasteri mogu sadržavati i CAG (AC) | (CC) mjesta. Kompleks SMAD3 / SMAD4 također se veže za elemente promotorskih gena koji reagiraju na TPA i imaju motivske sekvence TGAGTCAG.^[12]

Strukture

Aminokiselinska sekvenca

10	20	30	40	50
MDNMSITNTP	TSNDACLSIV	HSLMCHRQGG	ESETFAKRAI	ESLVKKLKEK
KDELDSLITA	ITTNGAHPSK	CVTIQRTLDG	RLQVAGRKGF	PHVIYARLWR
WPDLHKNELK	HVKYCQYAFD	LKCDSVCVNP	YHYERVVSPG	IDLSGLTLQS
NAPSSMMVKD	EYVHDFEGQP	SLSTEGHSIQ	TIQHPPSNRA	STETYSTPAL
LAPSESNATS	TANFPNIPVA	STSQPASILG	GSHSEGLLQI	ASGPQPGQQQ
NGFTGQPATY	HHNSTTTWTG	SRTAPYTPNL	PHHQNGHLQH	HPPMPPHPGH
YWPVHNELAF	QPPISNHPAP	EYWCSIAYFE	MDVQVGETFK	VPSSCPIVTV
DGYVDPSGGD	RFCLGQLSNV	HRTEAIERAR	LHIGKGVQLE	CKGEGDVWVR
CLSDHAVFVQ	SYYLDREAGR	APGDAVHKIY	PSAYIKVFDL	RQCHRQMQQQ
AATAQAAAAA	QAAAVAGNIP	GPGSVGGIAP	AISLSAAAGI	GVDDLRRLCI
LRMSFVKGWG	PDYPRQSIKE	TPCWIEIHLH	RALQLLDEVL	HTMPIADPQP
LD

Simboli

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

Kompleksi domena MH1 sa motivima DNK

Prva struktura SMAD4 vezana za DNK bio je kompleks s palindromskim motivom GTCTAGAC..^[13] Nedavno su određene i strukture SMAD4 MH1 domena, vezane za nekoliko 5GC motiva. U svim kompleksima, interakcija s DNK uključuje kunzerviranu β-ukosnicu MH1 domena. Ukosnica je djelimično fleksibilna u rastvoru, pa sa visokim stupanjem konformacijske fleksibilnosti omogućava prepoznavanje različitih sekvenci od 5 bp. Do efikasne interakcije sa GC-mjestima dolazi samo ako se G-nukleotid nalazi duboko u glavnom skupu i uspostavlja vodikove veze sa guaninskom grupom Arg81. Ova interakcija olakšava komplementarni površinski kontakt između ukosnice koja veže Smad DNK i glavne račve DNK. Druge direktne interakcije uključuju Lys88 i Gln83. Kristalna struktura rendgenskih zraka SMAD4 MH1 domena kod Trichoplax adhaerens , vezanih za motiv GGCGC, ukazuje na visoku konzerviranost ove interakcije u metazoama.^[11]

SMAD4 MH1 domen vezan za GGCT motiv DNK, iz 5MEZ.

Pogled izbliza na domen SMAD4 MH1 vezanog za motiv GGCGC DNK, iz 5MEY

SMAD4 MH1 domen, vezana za motiv GGCGC DNK, iz 5MEY.

Kompleksi domena MH2

Domen MH2, koji odgovara C-kraju, odgovorna je za prepoznavanje receptora i povezivanje s drugim SMAD-ovima. Interakcija je sa R-SMADS MH2 domenom i formira heterodimere i heterotrimere. Neke tumorske mutacije otkrivene u SMAD4 pojačavaju interakcije između MH1 i MH2 domena.^[14]

Nomenklatura i porijeklo imena

SMAD-ovi su visoko konzervirani po vrstama, posebno na N-terminalu MH1-domena i C-terminalu MH2-domena. SMAD-ovi proteini su homolozi i proteina MADkod Drosophila i protein SMA Caenorhabditis elegans. Ime je kombinacija oboje. Tokom istraživanja Drosophila utvrđeno je da mutacija gena MAD kod reakcije majke potiskuje gen dekapentaplegije u embrionu. Dodana je fraza "majke protiv", jer majke često formiraju strukture koje se protive raznim pitanjima, npr. majke protiv vožnje u pijanom stanju (MADD), što odražava "poboljšanje majčinog učinka dpp" ^[15] i zasnovano na tradiciji neobičnog imenovanja unutar istraživačke zajednice.^[16] SMAD4 je poznat i kao DPC4, JIP ili MADH4.

Funkcija i mehanizam djelovanja

SMAD4 je protein definiran kao bitni efektor u SMAD putu. SMAD4 služi kao posrednik između ivanćelijskih faktora rasta iz porodice TGFβ i gena unutar ćelijsog jedra. Skraćenica ko u ko-SMAD znači zajednički posrednik (koposrednik) . SMAD4 je također definiran kao pretvarač signala.

U TGF-β putu, TGF-β dimere prepoznaje transmembranski receptor, poznat kao receptor tipa II. Kada se receptor tipa II aktivira vezanjem TGF-β, fosforilira receptor tipa I. Receptor tipa I je također receptor na površini ćelije. Ovaj receptor zatim fosforilira SMAD-ove (R-SMAD), reguliran unutarćelijskim receptorima kao što su SMAD2 ili SMAD3. Fosforilirani R-SMAD-ovi se zatim vežu za SMAD4. Asocijacija R-SMAD-SMAD4 je heteromerni kompleks. Ovaj će se kompleks premjestiti iz citoplazme u jedro: to je translokacija. Sa R-SMAD-ovima, SMAD4 može stvarati heterotrimerne, heteroheksamerne ili heterodimerne komplekse.

SMAD4 je supstrat Erk/MAPK-kinaze.^[17] and GSK3.^[18] Stimulacija puta FGF (faktor rasta fibroblasta) dovodi do fosforilacije SMAD4, pomoću Erk kanonskog MAPK-mjesta, smeštenog na treonin 277. Ova fosforilacija ima dvostruki učinak na aktivnost SMAD4. Prvo, omogućava da dostigne svoj vrhunac transkripcijske aktivnosti, aktiviranjem faktorom rasta reguliranog domena za aktivaciju transkripcije koja se nalazi u regiji SMAD4 linkera, SAD (Smad-Activation Domain)).^[19] Drugo, MAPK primari SMAD4-a za GSK3 posredovane fosforilacije koje uzrokuju inhibiciju transkripcije, a takođe generiraju fosfodegron koji se koristi kao mjesto pristajanja ubikvitinskih E3-ligaza beta-transducin ponavljajućih sadržaja (beta-TrCP), koji poliubikvitinira SMAD4 i razgrađuje ga u proteasomu.^[20] Predložena je fosforilacija SMAD4 GSK3 za regulaciju stabilnosti proteina, tokom napredovanja gušteračinog raka i karcinoma debelog crijeva.^[21]

U jedru, heteromerni kompleks veže promotore i stupa u interakciju s transkripcijskim aktivatorima. Kompleksi SMAD3/SMAD4 mogu direktno vezati SBE. Ove asocijacije su slabe i trebaju dodatne faktore transkripcije, kao što su članovi porodice AP-1, TFE3 i FoxG1, za regulaciju ekspresije gena.^[22]

Mnogi ligandi TGFβ-a koriste ovaj put, a zatim je SMAD4 uključen u mnoge ćelijske funkcije kao što su diferencijacija, apoptoza, gastrulacija, embriogeneza i ćelijski ciklus.

Klinički značaj

Genetički eksperimenti poput nokaut-gena (KO), koji se sastoje u modificiranju ili inaktivaciji gena, mogu se izvesti kako bi se vidjeli efekti disfunkcionalnog SMAD4 na ispitivani organizam. Eksperimenti se često izvode na kućnom mišu (Mus musculus).

Pokazano je da u mišjem KO SMAD4 , zrnaste ćelije, koje luče hormone i faktore rasta tokom razvoja oocita, podvrgavaju se prijevremenoj luteinizaciji i izražavaju niže nivoe receptora za stimuliranje folikula (FSHR) i viši nivoi receptora luteinizirajućeg hormona (LHR). To je dijelom moguće zbog oštećenja efekata morfogenetskog proteina kostiju-7, jer BMP-7 koristi signalni put SMAD4.^[23]^[24]

Delecije u genima koji kodiraju SMAD1 i SMAD5 također su povezane sa metastaznim tumorima granulastih ćelija kod miševa.^[25]

SMAD4 je često mutiran kod mnogih karcinoma. Mutacija se može naslijediti ili steći tokom životnog vijeka. Ako se naslijedi, utiče i na somatske ćelije i na ćelije reproduktivnih organa. Ako se mutacija SMAD 4 stekne (de novo), postojat će samo u određenim somatskim ćelijama. Zapravo, SMAD 4 ne sintetiziraju sve ćelije. Protein je prisutan u ćelijama organa kao što su koža, gušterača, debelo crijevo, maternica i u epitelu. Takođe ga proizvode i fibroblasti.

Funkcionalni SMAD 4 sudjeluje u regulaciji puta transdukcije TGF-β signala, koji negativno regulira rast epitelnih ćelija i vanćelijski matriks (ECM). Kada se promijeni struktura SMAD 4, ekspresija gena uključenih u rast ćelija više nije regulirana i ćelijskaa proliferacija može trajati bez ikakve inhibicije. Veliki broj ćelijskih dioba dovodi do stvaranja tumora, a zatim do multiploidnih kolorektumskih karcinoma i karcinom pankreasa. Nalazi se inaktiviran u najmanje 50% karcinoma gušterače.^[26]

Pokazalo se da somatske mutacije pronađene u humano ljudskom karcinomu domene MH1 SMAD 4 inhibiraju funkciju vezivanja DNK ovog domena.

Pronađen je i mutirani SMAD 4 kod osoba sa autosomno dominantnom bolešću sindrom juvenilne polipoze (JPS). JPS karakteriziraju hamartomatozni polipi u gastrointestinalnom traktu (GI). Ti polipi obično su benigni, ali su u većem riziku od razvoja gastrointestinalnog karcinoma, posebno karcinoma debelog crijeva. Utvrđeno je oko 60 mutacija koje uzrokuju JPS. Povezani su s proizvodnjom manjeg SMAD 4, s nedostajućim domenima koji sprečavaju protein da se veže za R-SMADS i stvara heteromerne komplekse.

Mutacije u SMAD4 (uglavnom supstitucije) mogu izazvati Myhreov sindrom, rijetki nasljedni poremećaj koji karakteriziraju mentalne smetnje, nizak rast, neobične crte lica i razne abnormalnosti kostiju.^[27]^[28]

Reference

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^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000024515 - Ensembl, maj 2017
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^ Pangas SA, Li X, Robertson EJ, Matzuk MM (Jun 2006). "Premature luteinization and cumulus cell defects in ovarian-specific Smad4 knockout mice". Molecular Endocrinology. 20 (6): 1406–22. doi:10.1210/me.2005-0462. PMID 16513794.
^ Middlebrook BS, Eldin K, Li X, Shivasankaran S, Pangas SA (2009). "Smad1-Smad5 ovarian conditional knockout mice develop a disease profile similar to the juvenile form of human granulosa cell tumors". Endocrinology. 150 (12): 5208–17. doi:10.1210/en.2009-0644. PMC 2819741. PMID 19819941.
^ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th izd.). St. Louis, Mo: Elsevier Saunders. ISBN 0-7216-0187-1.
^ "Growth-Mental Deficiency Syndrome of Myhre". National Organization for rare disorders. Arhivirano s originala, 2. 4. 2015. Pristupljeno 6. 6. 2021.
^ Caputo V, Bocchinfuso G, Castori M, Traversa A, Pizzuti A, Stella L, Grammatico P, Tartaglia M (Jul 2014). "Novel SMAD4 mutation causing Myhre syndrome". American Journal of Medical Genetics Part A. 164A (7): 1835–40. doi:10.1002/ajmg.a.36544. PMID 24715504. S2CID 5294309.

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[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000141646 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000024515 - Ensembl, maj 2017

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[25] Middlebrook BS, Eldin K, Li X, Shivasankaran S, Pangas SA (2009). "Smad1-Smad5 ovarian conditional knockout mice develop a disease profile similar to the juvenile form of human granulosa cell tumors". Endocrinology. 150 (12): 5208–17. doi:10.1210/en.2009-0644. PMC 2819741. PMID 19819941.

[isbn0-7216-0187-1-26] Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th izd.). St. Louis, Mo: Elsevier Saunders. ISBN 0-7216-0187-1.

[27] "Growth-Mental Deficiency Syndrome of Myhre". National Organization for rare disorders. Arhivirano s originala, 2. 4. 2015. Pristupljeno 6. 6. 2021.

[28] Caputo V, Bocchinfuso G, Castori M, Traversa A, Pizzuti A, Stella L, Grammatico P, Tartaglia M (Jul 2014). "Novel SMAD4 mutation causing Myhre syndrome". American Journal of Medical Genetics Part A. 164A (7): 1835–40. doi:10.1002/ajmg.a.36544. PMID 24715504. S2CID 5294309.

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