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Sci Rep. 2019 Mar 11;9(1):4155. doi: 10.1038/s41598-019-40697-1.

Computational analysis of the evolutionarily conserved Missing In Metastasis/Metastasis Suppressor 1 gene predicts novel interactions, regulatory regions and transcriptional control.

Author information

1
Institute of Biomedicine, and MediCity Research Laboratories, University of Turku, Tykistökatu 6A, 20520, Turku, Finland. petar.petrov@utu.fi.
2
Institute of Biomedicine, and MediCity Research Laboratories, University of Turku, Tykistökatu 6A, 20520, Turku, Finland.
3
Division of Genetics and Genomics, The Roslin Institute and R(D)SVS, University of Edinburgh, Roslin, Easter Bush campus, Midlothian, EH25 9RG, United Kingdom.
4
Unit of B Cell Neoplasia, Division of Molecular Oncology, IRCCS, San Raffaele Scientific Institute, Milano, Italy.
5
Università Vita-Salute San Raffaele, Milan, Italy.
6
Strategic Research Program on CLL, Division of Experimental Oncology, IRCCS, San Raffaele Scientific Institute, Milano, Italy.
7
University of Queensland, St. Lucia, QLD, 4072, Australia.
8
Institute of Biomedicine, and MediCity Research Laboratories, University of Turku, Tykistökatu 6A, 20520, Turku, Finland. pieta.mattila@utu.fi.

Abstract

Missing in Metastasis (MIM), or Metastasis Suppressor 1 (MTSS1), is a highly conserved protein, which links the plasma membrane to the actin cytoskeleton. MIM has been implicated in various cancers, however, its modes of action remain largely enigmatic. Here, we performed an extensive in silico characterisation of MIM to gain better understanding of its function. We detected previously unappreciated functional motifs including adaptor protein (AP) complex interaction site and a C-helix, pointing to a role in endocytosis and regulation of actin dynamics, respectively. We also identified new functional regions, characterised with phosphorylation sites or distinct hydrophilic properties. Strong negative selection during evolution, yielding high conservation of MIM, has been combined with positive selection at key sites. Interestingly, our analysis of intra-molecular co-evolution revealed potential regulatory hotspots that coincided with reduced potentially pathogenic polymorphisms. We explored databases for the mutations and expression levels of MIM in cancer. Experimentally, we focused on chronic lymphocytic leukaemia (CLL), where MIM showed high overall expression, however, downregulation on poor prognosis samples. Finally, we propose strong conservation of MTSS1 also on the transcriptional level and predict novel transcriptional regulators. Our data highlight important targets for future studies on the role of MIM in different tissues and cancers.

PMID:
30858428
DOI:
10.1038/s41598-019-40697-1
Free PMC Article

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