Maspin (mammaryserineproteaseinhibitor) is aprotein that in humans is encoded by theSERPINB5gene.[5] This protein belongs to theserpin (serineproteaseinhibitor) superfamily.[5]SERPINB5 was originally reported to function as atumor suppressor gene in epithelial cells, suppressing the ability ofcancer cells to invade andmetastasize 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 ofgene 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.
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 includingphagocytosis,coagulation, andfibrinolysis.[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 anacyl 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 asuicide inhibitor of the protease.[11] This transition does not occur in serpins that lack inhibitory activity.[10]
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]
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 suppressorPHLPP1.[8]
^abZou 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.PMID8290962.
^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.PMID14985257.S2CID10572194.
^abcSager R, Sheng S, Pemberton P, Hendrix MJ (1996). "Maspin: A Tumor Suppressing Serpin".Attempts to Understand Metastasis Formation I. Current Topics in Microbiology and Immunology, vol. 213/1. Vol. 213/1. pp. 51–64.doi:10.1007/978-3-642-61107-0_4.ISBN978-3-642-64697-3.PMID8814994.
^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.PMID17001697.S2CID30396431.
Pemberton PA, Tipton AR, Pavloff N, et al. (1998). "Maspin is an intracellular serpin that partitions into secretory vesicles and is present at the cell surface".J. Histochem. Cytochem.45 (12):1697–706.doi:10.1177/002215549704501213.PMID9389773.S2CID23938193.
Xia W, Lau YK, Hu MC, et al. (2000). "High tumoral maspin expression is associated with improved survival of patients with oral squamous cell carcinoma".Oncogene.19 (20):2398–403.doi:10.1038/sj.onc.1203535.PMID10828881.S2CID9319721.
Biliran H, Sheng S (2002). "Pleiotrophic inhibition of pericellular urokinase-type plasminogen activator system by endogenous tumor suppressive maspin".Cancer Res.61 (24):8676–82.PMID11751384.
Dokras A, Gardner LM, Kirschmann DA, et al. (2002). "The tumour suppressor gene maspin is differentially regulated in cytotrophoblasts during human placental development".Placenta.23 (4):274–80.doi:10.1053/plac.2001.0784.PMID11969337.
