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STC2

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STC2
Identifiers
AliasesSTC2, STC-2, STCRP, stanniocalcin 2
External IDsOMIM: 603665; MGI: 1316731; HomoloGene: 2753; GeneCards: STC2; OMA:STC2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

8614

20856

Ensembl

ENSG00000113739

ENSMUSG00000020303

UniProt

O76061

O88452

RefSeq (mRNA)

NM_003714

NM_011491

RefSeq (protein)

NP_003705

NP_035621

Location (UCSC)Chr 5: 173.31 – 173.33 MbChr 11: 31.31 – 31.32 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Stanniocalcin-2 is a protein that in humans is encoded by the STC2 gene.[5][6][7]

This gene encodes a secreted, homodimeric glycoprotein that is expressed in a wide variety of tissues and may have autocrine or paracrine functions. The encoded protein has 10 of its 15 cysteine residues conserved among stanniocalcin family members and is phosphorylated by casein kinase 2 exclusively on its serine residues.

Its C-terminus contains a cluster of histidine residues which may interact with metal ions. The protein may play a role in the regulation of renal and intestinal calcium and phosphate transport, cell metabolism, or cellular calcium/phosphate homeostasis. Constitutive overexpression of human stanniocalcin 2 in mice resulted in pre-and postnatal growth restriction, reduced bone and skeletal muscle growth, and organomegaly. Expression of this gene is induced by estrogen and altered in some breast cancers.[7]

Stanniocalcin reduces bone growth[8] by modulating the activity of IGF1. One mechanism of IGF1 regulation is through IGFBP4 binding it in an inactive state. The protease PAPPA can then cleave this complex, releasing bioactive IGF1.[9] Stanniocalcin inhibits the activity of PAPPA in releasing active IGF1[9] through itself binding PAPPA,[10] thus preventing the release of active IGF1.

Differences in stanniocalcin expression have been directly linked to changes in skeletal size in a variety of species. For example, laboratory mice lacking STC2 are 10 to 15% larger than wild-type mice,[11] while mice expressing STC2 at elevated levels are 45% smaller.[8] In humans, the largest known coding variant affecting human height is a rare mutation reducing STC2 activity, yielding a 2 cm height increase in heterozygous carriers.[12] Additionally, domestic dog size is strongly predicted by a variant immediately adjacent to STC2, with almost all small dogs carrying a derived allele at this locus.[13] A further striking example is the stickleback, different populations of which have either increased or decreased the length of their dorsal and pelvic spines through modulation of STC2 expression.[14]


References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000113739 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020303 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Chang AC, Reddel RR (Nov 1998). "Identification of a second stanniocalcin cDNA in mouse and human: stanniocalcin 2". Mol Cell Endocrinol. 141 (1–2): 95–9. doi:10.1016/S0303-7207(98)00097-5. PMID 9723890. S2CID 28106090.
  6. ^ Ishibashi K, Miyamoto K, Taketani Y, Morita K, Takeda E, Sasaki S, Imai M (Nov 1998). "Molecular cloning of a second human stanniocalcin homologue (STC2)". Biochem Biophys Res Commun. 250 (2): 252–8. doi:10.1006/bbrc.1998.9300. PMID 9753616.
  7. ^ a b "Entrez Gene: STC2 stanniocalcin 2".
  8. ^ a b Gagliardi AD, Kuo EY, Raulic S, Wagner GF, DiMattia GE (January 2005). "Human stanniocalcin-2 exhibits potent growth-suppressive properties in transgenic mice independently of growth hormone and IGFs". Am J Physiol Endocrinol Metab. 288 (1): E92–105. doi:10.1152/ajpendo.00268.2004. PMID 15367391. S2CID 14827240.
  9. ^ a b Jepsen MR, Kløverpris S, Mikkelsen JH, Pedersen JH, Füchtbauer EM, Laursen LS, Oxvig C (February 2015). "Stanniocalcin-2 inhibits mammalian growth by proteolytic inhibition of the insulin-like growth factor axis". J Biol Chem. 290 (6): 3430–9. doi:10.1074/jbc.M114.611665. PMC 4319012. PMID 25533459.
  10. ^ Kobberø SD, Gajhede M, Mirza OA, Kløverpris S, Kjær TR, Mikkelsen JH, Boesen T, Oxvig C (October 2022). "Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism". Nat Commun. 13 (1): 6084. doi:10.1038/s41467-022-33698-8. PMC 9579167. PMID 36257932.
  11. ^ Chang AC, Hook J, Lemckert FA, McDonald MM, Nguyen MA, Hardeman EC, Little DG, Gunning PW, Reddel RR (May 2008). "The murine stanniocalcin 2 gene is a negative regulator of postnatal growth". Endocrinology. 149 (5): 2403–10. doi:10.1210/en.2007-1219. PMID 18258678. S2CID 43118428.
  12. ^ Marouli E, et al. (February 2017). "Rare and low-frequency coding variants alter human adult height". Nature. 542 (7640): 186–190. doi:10.1038/nature21039. PMC 5302847. PMID 28146470.
  13. ^ Rimbault M, Beale HC, Schoenebeck JJ, Hoopes BC, Allen JJ, Kilroy-Glynn P, Wayne RK, Sutter NB, Ostrander EA (December 2013). "Derived variants at six genes explain nearly half of size reduction in dog breeds". Genome Res. 23 (12): 1985–95. doi:10.1101/gr.157339.113. PMC 3847769. PMID 24026177.
  14. ^ Roberts Kingman GA, Lee D, Jones FC, Desmet D, Bell MA, Kingsley DM (August 2021). "Longer or shorter spines: Reciprocal trait evolution in stickleback via triallelic regulatory changes in Stanniocalcin2a". Proc Natl Acad Sci U S A. 118 (31). doi:10.1073/pnas.2100694118. PMC 8346906. PMID 34321354.

Further reading


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