STC2 explained

Stanniocalcin-2 is a protein that in humans is encoded by the STC2 gene.^{[1] [2] [3]}

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.^[3]

Stanniocalcin reduces bone growth^[4] 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.^[5] Stanniocalcin inhibits the activity of PAPPA in releasing active IGF1 through itself binding PAPPA,^[6] 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,^[7] while mice expressing STC2 at elevated levels are 45% smaller. 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.^[8] 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.^[9] 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.^[10]

Further reading

• DiMattia GE, Varghese R, Wagner GF . Molecular cloning and characterization of stanniocalcin-related protein . Mol. Cell. Endocrinol. . 146 . 1–2 . 137–40 . 1999 . 10022771 . 10.1016/S0303-7207(98)00163-4 . 27861622 .
• Moore EE, Kuestner RE, Conklin DC, etal . Stanniocalcin 2: characterization of the protein and its localization to human pancreatic alpha cells . Horm. Metab. Res. . 31 . 7 . 406–14 . 1999 . 10450831 . 10.1055/s-2007-978764 . 40695938 .
• Jellinek DA, Chang AC, Larsen MR, etal . Stanniocalcin 1 and 2 are secreted as phosphoproteins from human fibrosarcoma cells . Biochem. J. . 350 Pt 2 . 2. 453–61 . 2001 . 10947959 . 10.1042/0264-6021:3500453. 1221272 .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Ota T, Suzuki Y, Nishikawa T, etal . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . free .
• Beausoleil SA, Jedrychowski M, Schwartz D, etal . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proc. Natl. Acad. Sci. U.S.A. . 101 . 33 . 12130–5 . 2004 . 15302935 . 10.1073/pnas.0404720101 . 514446 . 2004PNAS..10112130B . free .
• Gagliardi AD, Kuo EY, Raulic S, etal . 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 . 2005 . 15367391 . 10.1152/ajpendo.00268.2004 . 14827240 .
• Luo CW, Pisarska MD, Hsueh AJ . Identification of a stanniocalcin paralog, stanniocalcin-2, in fish and the paracrine actions of stanniocalcin-2 in the mammalian ovary . Endocrinology . 146 . 1 . 469–76 . 2005 . 15486227 . 10.1210/en.2004-1197 . free .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Stelzl U, Worm U, Lalowski M, etal . A human protein-protein interaction network: a resource for annotating the proteome . Cell . 122 . 6 . 957–68 . 2005 . 16169070 . 10.1016/j.cell.2005.08.029 . 11858/00-001M-0000-0010-8592-0 . 8235923 . free .
• Otsuki T, Ota T, Nishikawa T, etal . Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries . DNA Res. . 12 . 2 . 117–26 . 2007 . 16303743 . 10.1093/dnares/12.2.117 . free .
• Esseghir S, Kennedy A, Seedhar P, etal . Identification of NTN4, TRA1, and STC2 as prognostic markers in breast cancer in a screen for signal sequence encoding proteins . Clin. Cancer Res. . 13 . 11 . 3164–73 . 2007 . 17545519 . 10.1158/1078-0432.CCR-07-0224 . 35660629 .
• Ichikawa T, Horie-Inoue K, Ikeda K, etal . Vitamin K2 induces phosphorylation of protein kinase A and expression of novel target genes in osteoblastic cells . J. Mol. Endocrinol. . 39 . 4 . 239–47 . 2007 . 17909264 . 10.1677/JME-07-0048 . free .

Notes and References

1. Chang AC, Reddel RR . Identification of a second stanniocalcin cDNA in mouse and human: stanniocalcin 2 . Mol Cell Endocrinol . 141 . 1–2 . 95–9 . Nov 1998 . 9723890 . 10.1016/S0303-7207(98)00097-5 . 28106090 .
2. Ishibashi K, Miyamoto K, Taketani Y, Morita K, Takeda E, Sasaki S, Imai M . Molecular cloning of a second human stanniocalcin homologue (STC2) . Biochem Biophys Res Commun . 250 . 2 . 252–8 . Nov 1998 . 9753616 . 10.1006/bbrc.1998.9300 .
3. Web site: Entrez Gene: STC2 stanniocalcin 2.
4. Gagliardi AD, Kuo EY, Raulic S, Wagner GF, DiMattia GE . 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 . January 2005 . 15367391 . 10.1152/ajpendo.00268.2004. 14827240 .
5. Jepsen MR, Kløverpris S, Mikkelsen JH, Pedersen JH, Füchtbauer EM, Laursen LS, Oxvig C . Stanniocalcin-2 inhibits mammalian growth by proteolytic inhibition of the insulin-like growth factor axis . J Biol Chem . 290 . 6 . 3430–9 . February 2015 . 25533459 . 4319012 . 10.1074/jbc.M114.611665 . free .
6. Kobberø SD, Gajhede M, Mirza OA, Kløverpris S, Kjær TR, Mikkelsen JH, Boesen T, Oxvig C . Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism . Nat Commun . 13 . 1 . 6084 . October 2022 . 36257932 . 9579167 . 10.1038/s41467-022-33698-8 . 2022NatCo..13.6084K .
7. Chang AC, Hook J, Lemckert FA, McDonald MM, Nguyen MA, Hardeman EC, Little DG, Gunning PW, Reddel RR . The murine stanniocalcin 2 gene is a negative regulator of postnatal growth . Endocrinology . 149 . 5 . 2403–10 . May 2008 . 18258678 . 10.1210/en.2007-1219 . 43118428 . free .
8. Marouli E, et al.. Rare and low-frequency coding variants alter human adult height . Nature . 542 . 7640 . 186–190 . February 2017 . 28146470 . 5302847 . 10.1038/nature21039 . 2017Natur.542..186M .
9. Rimbault M, Beale HC, Schoenebeck JJ, Hoopes BC, Allen JJ, Kilroy-Glynn P, Wayne RK, Sutter NB, Ostrander EA . Derived variants at six genes explain nearly half of size reduction in dog breeds . Genome Res . 23 . 12 . 1985–95 . December 2013 . 24026177 . 3847769 . 10.1101/gr.157339.113 .
10. Roberts Kingman GA, Lee D, Jones FC, Desmet D, Bell MA, Kingsley DM . Longer or shorter spines: Reciprocal trait evolution in stickleback via triallelic regulatory changes in Stanniocalcin2a . Proc Natl Acad Sci U S A . 118 . 31 . August 2021 . 34321354 . 8346906 . 10.1073/pnas.2100694118 . free . 2021PNAS..11800694R .