Maspin

Last updated
SERPINB5
Protein SERPINB5 PDB 1wz9.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SERPINB5 , PI5, maspin, serpin family B member 5
External IDs OMIM: 154790 MGI: 109579 HomoloGene: 20580 GeneCards: SERPINB5
Orthologs
SpeciesHumanMouse
Entrez

5268

20724

Ensembl

ENSG00000206075

ENSMUSG00000067006

UniProt

P36952

P70124

RefSeq (mRNA)

NM_002639

NM_009257
NM_001360853
NM_001360854

RefSeq (protein)

NP_002630

NP_033283
NP_001347782
NP_001347783

Location (UCSC) Chr 18: 63.48 – 63.51 Mb Chr 1: 106.79 – 106.81 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Maspin (mammary serine protease inhibitor) is a protein that in humans is encoded by the SERPINB5 gene. [5] This protein belongs to the serpin (serine protease inhibitor) superfamily. [5] SERPINB5 was originally reported to function as a tumor suppressor gene in epithelial cells, suppressing the ability of cancer cells to invade and metastasize to other tissues. [6] Furthermore, and consistent with an important biological function, Maspin knockout mice were reported to be non-viable, dying in early embryogenesis. [7] However, a subsequent study using viral transduction as a method of gene transfer (rather than single cell cloning) was not able to reproduce the original findings and found no role for maspin in tumour biology. [8] Furthermore, the latter study demonstrated that maspin knockout mice are viable and display no obvious phenotype. [8] These data are consistent with the observation that maspin is not expressed in early embryogenesis. [8] The precise molecular function of maspin is thus currently unknown.

Contents

Tissue distribution

Maspin is expressed in the skin, prostate, testis, intestine, tongue, lung, and the thymus. [5]

Serpin superfamily

Maspin is a member of the serpin superfamily of serine protease inhibitors. [5] The primary function of most members of this family is to regulate the breakdown of proteins by inhibiting the catalytic activity of proteinases. Through this mechanism of action, serpins regulate a number of cellular processes including phagocytosis, coagulation, and fibrinolysis. [9]

Serpins have a complex structure, a key component of which is the reactive site loop, RSL. [10] Inhibitory serpins transition between a stress and relaxed stage. The catalytic serine residue in the protease target attacks the stressed conformation of the RSL loop to form an acyl intermediate. The loop then undergoes a conformational change to the relaxed state irreversibly trapping the protease in an inactive state. Hence the serpin functions as a suicide inhibitor of the protease. [11] This transition does not occur in serpins that lack inhibitory activity. [10]

Function

Given its original reported role in cancer biology, [6] numerous studies have investigated a role for maspin in tumour metastasis. [12] However, to date no detailed molecular mechanism for maspin function in cell proliferation or tumour biology has been comprehensively described. Further, it is suggested that original reports of maspin as a tumor suppressor may reflect clonal artefacts rather than true maspin function. [8] Importantly, and in contrast to original reports, maspin knockout mice are viable, displaying no overt phenotype in the absence of suitable biological or environmental challenge. [8] Accordingly, the molecular function of maspin remains unclear.

From a structural perspective, maspin is a non-inhibitory and obligate intracellular member of the serpin superfamily. [13] Specifically, its RSL does not transition between a stressed and relaxed state following proteolytic cleavage. [14] This region is also shorter than the RSL loop in other serpins. Accordingly, in the absence of an obvious protease-related function, other targets of maspin have been suggested. For example, rather than being a protease inhibitor, maspin is proposed to function as an inhibitor of histone deacetylase 1 (HDAC1). [10] [15]

Clinical significance

A comprehensive analysis of maspin expression in breast cancer revealed no significant correlation between maspin expression and overall survival, distant metastasis-free survival or recurrence-free survival. [8] Changes in maspin expression may, however, reflect the expression status of the known tumour suppressor PHLPP1. [8]

Related Research Articles

<span class="mw-page-title-main">Serpin</span> Superfamily of proteins with similar structures and diverse functions

Serpins are a superfamily of proteins with similar structures that were first identified for their protease inhibition activity and are found in all kingdoms of life. The acronym serpin was originally coined because the first serpins to be identified act on chymotrypsin-like serine proteases. They are notable for their unusual mechanism of action, in which they irreversibly inhibit their target protease by undergoing a large conformational change to disrupt the target's active site. This contrasts with the more common competitive mechanism for protease inhibitors that bind to and block access to the protease active site.

A trypsin inhibitor (TI) is a protein and a type of serine protease inhibitor (serpin) that reduces the biological activity of trypsin by controlling the activation and catalytic reactions of proteins. Trypsin is an enzyme involved in the breakdown of many different proteins, primarily as part of digestion in humans and other animals such as monogastrics and young ruminants. Serpins – including trypsin inhibitors – are irreversible and suicide substrate-like inhibitors.

<span class="mw-page-title-main">Plasminogen activator inhibitor-2</span> Coagulation factor protein found in humans

Plasminogen activator inhibitor-2, a serine protease inhibitor of the serpin superfamily, is a coagulation factor that inactivates tissue plasminogen activator and urokinase. It is present in most cells, especially monocytes/macrophages. PAI-2 exists in two forms, a 60-kDa extracellular glycosylated form and a 43-kDa intracellular form.

<span class="mw-page-title-main">Alpha 1-antichymotrypsin</span> Protein-coding gene in the species Homo sapiens

Alpha 1-antichymotrypsin is an alpha globulin glycoprotein that is a member of the serpin superfamily. In humans, it is encoded by the SERPINA3 gene.

<span class="mw-page-title-main">KLK2</span> Protein-coding gene in the species Homo sapiens

Kallikrein-2 is a protein that in humans is encoded by the KLK2 gene, and is particularly associated with prostatic tissue.

<span class="mw-page-title-main">ST14</span> Protein-coding gene in the species Homo sapiens

Suppressor of tumorigenicity 14 protein, also known as matriptase, is a protein that in humans is encoded by the ST14 gene. ST14 orthologs have been identified in most mammals for which complete genome data are available.

<span class="mw-page-title-main">SERPINB3</span> Protein-coding gene in the species Homo sapiens

Serpin B3 is a protein that in humans is encoded by the SERPINB3 gene.

<span class="mw-page-title-main">KLK10</span> Protein-coding gene in the species Homo sapiens

Kallikrein-10 is a protein that in humans is encoded by the KLK10 gene.

<span class="mw-page-title-main">SERPINB9</span> Protein-coding gene in the species Homo sapiens

Serpin B9 is a protein that in humans is encoded by the SERPINB9 gene. PI9 belongs to the large superfamily of serine proteinase inhibitors (serpins), which bind to and inactivate serine proteinases. These interactions are involved in many cellular processes, including coagulation, fibrinolysis, complement fixation, matrix remodeling, and apoptosis .[supplied by OMIM]

<span class="mw-page-title-main">SERPINE2</span> Protein-coding gene in the species Homo sapiens

Glia-derived nexin is a protein that in humans is encoded by the SERPINE2 gene.

<span class="mw-page-title-main">SERPINB4</span> Protein-coding gene in the species Homo sapiens

Serpin B4 is a protein that in humans is encoded by the SERPINB4 gene.

<span class="mw-page-title-main">SERPINB6</span> Protein-coding gene in the species Homo sapiens

Serpin B6 is a protein that in humans is encoded by the SERPINB6 gene.

<span class="mw-page-title-main">LATS1</span> Protein-coding gene in the species Homo sapiens

Large tumor suppressor kinase 1 (LATS1) is an enzyme that in humans is encoded by the LATS1 gene.

<span class="mw-page-title-main">SERPINB1</span> Protein-coding gene in the species Homo sapiens

Leukocyte elastase inhibitor (LEI) also known as serpin B1 is a protein that in humans is encoded by the SERPINB1 gene. It is a member of the clade B serpins or ov-serpins founded by ovalbumin.

<span class="mw-page-title-main">HGFAC</span> Protein-coding gene in humans

Hepatocyte growth factor activator is a protein that in humans is encoded by the HGFAC gene.

<span class="mw-page-title-main">RECK</span> Protein-coding gene in the species Homo sapiens

Reversion-inducing-cysteine-rich protein with kazal motifs, also known as RECK, is a human gene, thought to be a metastasis suppressor.

<span class="mw-page-title-main">CST6 (gene)</span> Protein-coding gene in the species Homo sapiens

Cystatin-M is a protein that in humans is encoded by the CST6 gene.

<span class="mw-page-title-main">SERPINB8</span> Protein-coding gene in the species Homo sapiens

Serpin B8 is a protein that in humans is encoded by the SERPINB8 gene.

Myeloid and erythroid nuclear termination stage-specific protein (MENT) is a member of the serpin family of protease inhibitors, and participates in DNA and chromatin condensation. Alongside its ability to condense chromatin, MENT is also an effective inhibitor of the proteases cathepsin K, cathepsin L, and cathepsin V, all of which are cysteine proteases. As such, although MENT is structurally classified as a member of the serpin family, it is functionally termed a "cross-class inhibitor," as it is a cysteine rather than a serine protease inhibitor.

Uterine serpins are members of the A clade of the serine protease inhibitor (serpin) superfamily of proteins and are encoded by the SERPINA14 gene. Uterine serpins are produced by the endometrium of a restricted group of mammals under the influence of progesterone or estrogen. These proteins appear to be inactive protease inhibitors and may function during pregnancy to regulate immune function or participate in transplacental transport.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000206075 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000067006 - 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. 1 2 3 4 Khalkhali-Ellis Z (December 2006). "Maspin: the new frontier". Clin. Cancer Res. 12 (24): 7279–83. doi:10.1158/1078-0432.CCR-06-1589. PMC   3175762 . PMID   17189399.
  6. 1 2 Zou Z, Anisowicz A, Hendrix MJ, Thor A, Neveu M, Sheng S, Rafidi K, Seftor E, Sager R (1994). "Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells". Science. 263 (5146): 526–9. Bibcode:1994Sci...263..526Z. doi:10.1126/science.8290962. PMID   8290962.
  7. ↑ Gao F, Shi H, Daughty C, Cella N, Zhang M (2004). "Maspin plays an essential role in early embryonic development". Development. 131 (7): 1479–89. doi:10.1242/dev.01048. PMID   14985257.
  8. 1 2 3 4 5 6 7 Teoh SS, Vieusseux J, Prakash M, Berkowicz S, Luu J, Bird CH, Law RH, Rosado C, Price JT, Whisstock JC, Bird PI (January 2014). "Maspin is not required for embryonic development or tumour suppression". Nat Commun. 5: 3164. Bibcode:2014NatCo...5.3164T. doi:10.1038/ncomms4164. PMC   3905777 . PMID   24445777.
  9. ↑ Potempa J, Korzus E, Travis J (June 1994). "The serpin superfamily of proteinase inhibitors: structure, function, and regulation". J. Biol. Chem. 269 (23): 15957–60. doi: 10.1016/S0021-9258(17)33954-6 . PMID   8206889.
  10. 1 2 3 Sager R, Sheng S, Pemberton P, Hendrix MJ (1996). "Maspin: a tumor suppressing serpin". Curr. Top. Microbiol. Immunol. Current Topics in Microbiology 213/I and Immunology. 213 (1): 51–64. doi:10.1007/978-3-642-61107-0_4. ISBN   978-3-642-64697-3. PMID   8814994.
  11. ↑ Bailey CM, Khalkhali-Ellis Z, Seftor EA, Hendrix MJ (December 2006). "Biological functions of maspin". J. Cell. Physiol. 209 (3): 617–24. doi:10.1002/jcp.20782. PMID   17001697. S2CID   30396431.
  12. ↑ Luo JL, Tan W, Ricono JM, Korchynskyi O, Zhang M, Gonias SL, et al. (2007). "Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin". Nature. 446 (7136): 690–4. Bibcode:2007Natur.446..690L. doi:10.1038/nature05656. PMID   17377533. S2CID   4417226.
  13. ↑ Teoh SS, Whisstock JC, Bird PI (2010). "Maspin (SERPINB5) is an obligate intracellular serpin". J Biol Chem. 285 (14): 10862–9. doi: 10.1074/jbc.M109.073171 . PMC   2856292 . PMID   20123984.
  14. ↑ Pemberton PA, Wong DT, Gibson HL, Kiefer MC, Fitzpatrick PA, Sager R, et al. (1995). "The tumor suppressor maspin does not undergo the stressed to relaxed transition or inhibit trypsin-like serine proteases. Evidence that maspin is not a protease inhibitory serpin". J Biol Chem. 270 (26): 15832–7. doi: 10.1074/jbc.270.26.15832 . PMID   7797587.
  15. ↑ Lonardo F, Li X, Kaplun A, Soubani A, Sethi S, Gadgeel S, Sheng S (June 2010). "The natural tumor suppressor protein maspin and potential application in non small cell lung cancer". Curr. Pharm. Des. 16 (16): 1877–81. doi:10.2174/138161210791208974. PMC   2908495 . PMID   20337574.

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