Maspin

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Serpin peptidase inhibitor, clade B (ovalbumin), member 5
Protein SERPINB5 PDB 1wz9.png
PDB rendering based on 1wz9.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols SERPINB5 ; PI5; maspin
External IDs OMIM154790 MGI109579 HomoloGene20580 GeneCards: SERPINB5 Gene
RNA expression pattern
PBB GE SERPINB5 204855 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5268 20724
Ensembl ENSG00000206075 ENSMUSG00000067006
UniProt P36952 P70124
RefSeq (mRNA) NM_002639 NM_009257
RefSeq (protein) NP_002630 NP_033283
Location (UCSC) Chr 18:
61.14 – 61.17 Mb
Chr 1:
106.86 – 106.88 Mb
PubMed search [1] [2]

Maspin (mammary serine protease inhibitor) is a protein that in humans is encoded by the SERPINB5 gene.[1] This protein belongs to the serpin (serine protease inhibitor) superfamily.[1] 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.[2] Furthermore, and consistent with an important biological function, Maspin knockout mice were reported to be non-viable, dying in early embryogenesis.[3] 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.[4] Furthermore, the latter study demonstrated that maspin knockout mice are viable and display no obvious phenotype.[4] These data are consistent with the observation that maspin is not expressed in early embryogenesis.[4] The precise molecular function of maspin is thus currently unknown.

Tissue distribution[edit]

Maspin is expressed in the skin, prostate, testis, intestine, tongue, lung, and the thymus.[1]

Serpin superfamily[edit]

Main article: serpin

Maspin is a member of the serpin superfamily of serine protease inhibitors.[1] 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.[5]

Serpins have a complex structure, a key component of which is the reactive site loop, RSL.[6] 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.[7] This transition does not occur in serpins that lack inhibitory activity.[6]

Function[edit]

Given its original reported role in cancer biology,[2] numerous studies have investigated a role for maspin in tumour metastasis.[8] 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.[4] 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.[4] 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.[9] Specifically, its RSL does not transition between a stressed and relaxed state following proteolytic cleavage.[10] 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).[6][11]

Clinical significance[edit]

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.[4] Changes in maspin expression may, however, reflect the expression status of the known tumour suppressor PHLPP1.[4]

References[edit]

  1. ^ a b c d 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. 
  2. ^ a b 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. doi:10.1126/science.8290962. PMID 8290962. 
  3. ^ 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. 
  4. ^ a b c d e f g 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. doi:10.1038/ncomms4164. PMID 24445777. 
  5. ^ 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. PMID 8206889. 
  6. ^ a b c Sager R, Sheng S, Pemberton P, Hendrix MJ (1996). "Maspin: a tumor suppressing serpin". Curr. Top. Microbiol. Immunol. 213 (1): 51–64. doi:10.1007/978-3-642-61107-0_4. PMID 8814994. 
  7. ^ 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. 
  8. ^ 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. doi:10.1038/nature05656. PMID 17377533. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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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