O60383 (GDF9_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Growth/differentiation factor 9
Short name=GDF-9

Gene names

Name:

GDF9

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	454 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Required for ovarian folliculogenesis. Promotes primordial follicle development. Stimulates granulosa cell proliferation. Promotes cell transition from G0/G1 to S and G2/M phases, through an increase of CCND1 and CCNE1 expression, and RB1 phosphorylation. It regulates STAR expression and cAMP-dependent progesterone release in granulosa and thecal cells. Attenuates the suppressive effects of activin A on STAR expression and progesterone production by increasing the expression of inhibin B. It suppresses FST and FSTL3 production in granulosa-lutein cells. Ref.4 Ref.7 Ref.9 Ref.10 Ref.11
Subunit structure	Homodimer or heterodimer Potential. But, in contrast to other members of this family, cannot be disulfide-linked By similarity.
Subcellular location	Secreted By similarity.
Tissue specificity	Expressed in ovarian granulosa cells. Present in oocytes of primary follicles (at protein level). Ref.3 Ref.4
Post-translational modification	Phosphorylated; phosphorylation is critical for GDF9 function. In vitro, can be phosphorylated by CK at Ser-325. Ref.6 Ref.8
Involvement in disease	Altered GDF9 function may be involved in ovarian disorders. Rare variants in GDF9 have been found in patients with premature ovarian failure and mothers of dizygotic twins.
Miscellaneous	Ovarian physiology and fertility are controlled by endocrine and paracrine signals. These act in a species-dependent manner and determine the ovulation quota in different mammalian species. While humans, and mammals such as the cow or red deer, normally ovulate only one egg per cycle, other mammals such as mouse and pig can ovulate in excess of ten per cycle. The mechanisms that regulate the species-specific differences in the number of follicles that go onto ovulate during each reproductive cycle are poorly understood. According to Ref.12, mRNA expression levels of GDF9 and BMP15 are tightly co-regulated within each species and influence species-specific ovulation-rates.
Sequence similarities	Belongs to the TGF-beta family.

Ontologies

Keywords
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Domain	Signal
Molecular function	Cytokine Growth factor
PTM	Cleavage on pair of basic residues Disulfide bond Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	female gamete generation Traceable author statement PubMed 7760846PubMed 8849725. Source: ProtInc negative regulation of cell growth Inferred from electronic annotation. Source: Compara oocyte growth Inferred from electronic annotation. Source: Compara positive regulation of cell proliferation Inferred from direct assay Ref.7. Source: UniProtKB regulation of progesterone secretion Inferred from direct assay Ref.4. Source: UniProtKB transforming growth factor beta receptor signaling pathway Traceable author statement PubMed 7760846. Source: ProtInc
Cellular_component	extracellular space Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	growth factor activity Traceable author statement PubMed 8849725. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 24	24	Potential
	Propeptide	25 – 319	295	Potential		PRO_0000033980
	Chain	320 – 454	135	Growth/differentiation factor 9		PRO_0000033981
Amino acid modifications
	Modified residue	25	1	Phosphoserine Potential
	Glycosylation	106	1	N-linked (GlcNAc...) Potential
	Glycosylation	163	1	N-linked (GlcNAc...) Potential
	Glycosylation	236	1	N-linked (GlcNAc...) Potential
	Glycosylation	255	1	N-linked (GlcNAc...) Potential
	Glycosylation	268	1	N-linked (GlcNAc...) Potential
	Glycosylation	338	1	N-linked (GlcNAc...) Potential
	Disulfide bond	353 ↔ 419		By similarity
	Disulfide bond	382 ↔ 451		By similarity
	Disulfide bond	386 ↔ 453		By similarity
Natural variations
	Natural variant	57	1	D → Y. Ref.18 Corresponds to variant rs138136756 [ dbSNP | Ensembl ].		VAR_066934
	Natural variant	67	1	K → E in some patients with premature ovarian failure. Ref.13		VAR_058945
	Natural variant	103	1	P → S. Ref.15 Ref.16 Corresponds to variant rs61754583 [ dbSNP | Ensembl ].		VAR_066935
	Natural variant	121	1	T → I. Ref.15 Corresponds to variant rs149821575 [ dbSNP | Ensembl ].		VAR_066936
	Natural variant	146	1	R → C. Ref.17 Corresponds to variant rs76349024 [ dbSNP | Ensembl ].		VAR_066937
	Natural variant	186	1	S → Y in a patient with premature ovarian failure. Ref.14		VAR_058946
	Natural variant	216	1	V → M in two patients with premature ovarian failure. Ref.13		VAR_058947
	Natural variant	238	1	T → A in a patient with premature ovarian failure. Ref.17		VAR_066938
	Natural variant	374	1	P → L Rare variant found in mothers of dizygotic twins. Ref.15		VAR_066939
	Natural variant	428	1	S → T. Ref.17 Corresponds to variant rs118080183 [ dbSNP | Ensembl ].		VAR_066940
	Natural variant	454	1	R → C. Ref.15 Corresponds to variant rs61754582 [ dbSNP | Ensembl ].		VAR_066941

Sequences

	Sequence		Length	Mass (Da)
	O60383 [UniParc]. Last modified August 1, 1998. Version 1. Checksum: 94EA366E90CDBC27	FASTA	454	51,444
	10 20 30 40 50 60 MARPNKFLLW FCCFAWLCFP ISLGSQASGG EAQIAASAEL ESGAMPWSLL QHIDERDRAG 70 80 90 100 110 120 LLPALFKVLS VGRGGSPRLQ PDSRALHYMK KLYKTYATKE GIPKSNRSHL YNTVRLFTPC 130 140 150 160 170 180 TRHKQAPGDQ VTGILPSVEL LFNLDRITTV EHLLKSVLLY NINNSVSFSS AVKCVCNLMI 190 200 210 220 230 240 KEPKSSSRTL GRAPYSFTFN SQFEFGKKHK WIQIDVTSLL QPLVASNKRS IHMSINFTCM 250 260 270 280 290 300 KDQLEHPSAQ NGLFNMTLVS PSLILYLNDT SAQAYHSWYS LHYKRRPSQG PDQERSLSAY 310 320 330 340 350 360 PVGEEAAEDG RSSHHRHRRG QETVSSELKK PLGPASFNLS EYFRQFLLPQ NECELHDFRL 370 380 390 400 410 420 SFSQLKWDNW IVAPHRYNPR YCKGDCPRAV GHRYGSPVHT MVQNIIYEKL DSSVPRPSCV 430 440 450 PAKYSPLSVL TIEPDGSIAY KEYEDMIATK CTCR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The DNA sequence and comparative analysis of human chromosome 5." Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S. , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M. Nature 431:268-274(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"Human growth differentiation factor 9 (GDF-9) and its novel homolog GDF-9B are expressed in oocytes during early folliculogenesis." Aaltonen J., Laitinen M.P., Vuojolainen K., Jaatinen R., Horelli-Kuitunen N., Seppae L., Louhio H., Tuuri T., Sjoeberg J., Buetzow R., Hovatta O., Dale L., Ritvos O. J. Clin. Endocrinol. Metab. 84:2744-2750(1999) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY.
[4]	"Growth differentiation factor-9 inhibits 3'5'-adenosine monophosphate-stimulated steroidogenesis in human granulosa and theca cells." Yamamoto N., Christenson L.K., McAllister J.M., Strauss J.F. III J. Clin. Endocrinol. Metab. 87:2849-2856(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS REGULATOR OF PROGESTERONE RELEASE, TISSUE SPECIFICITY.
[5]	Erratum Yamamoto N., Christenson L.K., McAllister J.M., Strauss J.F. III J. Clin. Endocrinol. Metab. 87:4495-4495(2002)
[6]	"Phosphorylation of bone morphogenetic protein-15 and growth and differentiation factor-9 plays a critical role in determining agonistic or antagonistic functions." McMahon H.E., Sharma S., Shimasaki S. Endocrinology 149:812-817(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION.
[7]	"Effects of growth differentiation factor 9 on cell cycle regulators and ERK42/44 in human granulosa cell proliferation." Huang Q., Cheung A.P., Zhang Y., Huang H.F., Auersperg N., Leung P.C. Am. J. Physiol. 296:E1344-E1353(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN GRANULOSA CELLS PROLIFERATION.
[8]	"Golgi apparatus casein kinase phosphorylates bioactive Ser-6 of bone morphogenetic protein 15 and growth and differentiation factor 9." Tibaldi E., Arrigoni G., Martinez H.M., Inagaki K., Shimasaki S., Pinna L.A. FEBS Lett. 584:801-805(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-325 BY CK, MASS SPECTROMETRY.
[9]	"Growth differentiation factor 9 reverses activin A suppression of steroidogenic acute regulatory protein expression and progesterone production in human granulosa-lutein cells." Shi F.T., Cheung A.P., Klausen C., Huang H.F., Leung P.C. J. Clin. Endocrinol. Metab. 95:E172-E180(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS REGULATOR OF STAR EXPRESSION AND PROGESTERONE RELEASE.
[10]	"Growth differentiating factor 9 (GDF9) and bone morphogenetic protein 15 both activate development of human primordial follicles in vitro, with seemingly more beneficial effects of GDF9." Kedem A., Fisch B., Garor R., Ben-Zaken A., Gizunterman T., Felz C., Ben-Haroush A., Kravarusic D., Abir R. J. Clin. Endocrinol. Metab. 96:E1246-E1254(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PRIMORDIAL FOLLICLE DEVELOPMENT.
[11]	"Growth differentiation factor 9 (GDF9) suppresses follistatin and follistatin-like 3 production in human granulosa-lutein cells." Shi F.T., Cheung A.P., Huang H.F., Leung P.C. PLoS ONE 6:E22866-E22866(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[12]	"The ratio of growth differentiation factor 9: bone morphogenetic protein 15 mRNA expression is tightly co-regulated and differs between species over a wide range of ovulation rates." Crawford J.L., McNatty K.P. Mol. Cell. Endocrinol. 348:339-343(2012) [PubMed] [Europe PMC] [Abstract] Cited for: SPECIES-SPECIFIC OVULATION RATE DETERMINATION.
[13]	"Mutational screening of the coding region of growth differentiation factor 9 gene in Indian women with ovarian failure." Dixit H., Rao L.K., Padmalatha V., Kanakavalli M., Deenadayal M., Gupta N., Chakravarty B., Singh L. Menopause 12:749-754(2005) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS GLU-67 AND MET-216.
[14]	"Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure." Laissue P., Christin-Maitre S., Touraine P., Kuttenn F., Ritvos O., Aittomaki K., Bourcigaux N., Jacquesson L., Bouchard P., Frydman R., Dewailly D., Reyss A.-C., Jeffery L., Bachelot A., Massin N., Fellous M., Veitia R.A. Eur. J. Endocrinol. 154:739-744(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT TYR-186.
[15]	"Novel variants in growth differentiation factor 9 in mothers of dizygotic twins." Palmer J.S., Zhao Z.Z., Hoekstra C., Hayward N.K., Webb P.M., Whiteman D.C., Martin N.G., Boomsma D.I., Duffy D.L., Montgomery G.W. J. Clin. Endocrinol. Metab. 91:4713-4716(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS SER-103; ILE-121; LEU-374 AND CYS-454, POSSIBLE INVOLVEMENT IN OVARIAN DISORDERS.
[16]	"Growth differentiating factor-9 mutations may be associated with premature ovarian failure." Kovanci E., Rohozinski J., Simpson J.L., Heard M.J., Bishop C.E., Carson S.A. Fertil. Steril. 87:143-146(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SER-103, POSSIBLE INVOLVEMENT IN PREMATURE OVARIAN FAILURE.
[17]	"Analyses of GDF9 mutation in 100 Chinese women with premature ovarian failure." Zhao H., Qin Y., Kovanci E., Simpson J.L., Chen Z.J., Rajkovic A. Fertil. Steril. 88:1474-1476(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CYS-146; ALA-238 AND THR-428.
[18]	"Analyses of growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) mutation in Chinese women with premature ovarian failure." Wang B., Wen Q., Ni F., Zhou S., Wang J., Cao Y., Ma X. Clin. Endocrinol. (Oxf.) 72:135-136(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT TYR-57.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AC004500 Genomic DNA. Translation: AAC08450.1. BC096228 mRNA. Translation: AAH96228.1. BC096229 mRNA. Translation: AAH96229.1. BC096230 mRNA. Translation: AAH96230.1. BC096231 mRNA. Translation: AAH96231.1.
IPI	IPI00029127.
RefSeq	NP_005251.1. NM_005260.3.
UniGene	Hs.25022.
3D structure databases
ProteinModelPortal	O60383.
ModBase	Search...
Protein-protein interaction databases
IntAct	O60383. 35 interactions.
MINT	MINT-1430245.
STRING	9606.ENSP00000296875.
PTM databases
PhosphoSite	O60383.
Proteomic databases
PaxDb	O60383.
PRIDE	O60383.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000296875; ENSP00000296875; ENSG00000164404. ENST00000378673; ENSP00000367942; ENSG00000164404.
GeneID	2661.
KEGG	hsa:2661.
UCSC	uc003kxz.1. human.
Organism-specific databases
CTD	2661.
GeneCards	GC05M132196.
HGNC	HGNC:4224. GDF9.
MIM	601918. gene.
neXtProt	NX_O60383.
PharmGKB	PA28639.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG261730.
HOGENOM	HOG000073526.
HOVERGEN	HBG004660.
InParanoid	O60383.
KO	K05498.
OMA	YEDMIAT.
OrthoDB	EOG48WC1X.
PhylomeDB	O60383.
Gene expression databases
ArrayExpress	O60383.
Bgee	O60383.
CleanEx	HS_GDF9.
Genevestigator	O60383.
GermOnline	ENSG00000164404. Homo sapiens.
Family and domain databases
InterPro	IPR015617. Growth_differentiation_fac-9. IPR001839. TGF-b_C. IPR015615. TGF-beta-rel. IPR017948. TGFb_CS. [Graphical view]
PANTHER	PTHR11848. PTHR11848. 1 hit. PTHR11848:SF19. PTHR11848:SF19. 1 hit.
Pfam	PF00019. TGF_beta. 1 hit. [Graphical view]
SMART	SM00204. TGFB. 1 hit. [Graphical view]
PROSITE	PS00250. TGF_BETA_1. 1 hit. PS51362. TGF_BETA_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	2661.
NextBio	10504.
SOURCE	Search...

Entry information

Entry name

GDF9_HUMAN

Accession

Primary (citable) accession number: O60383
Secondary accession number(s): Q4VAW5

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	August 1, 1998
Last modified:	May 1, 2013
This is version 104 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.