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Kinase-Independent Functions of MASTL in Cancer: a New Perspective on MASTL Targeting

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Kinase-Independent Functions of MASTL in Cancer: a New Perspective on MASTL Targeting cells Perspective Kinase-Independent Functions of MASTL in Cancer: A New Perspective on MASTL Targeting 1, 1, 1, James Ronald William Conway y , Elisa Närvä y, Maria Emilia Taskinen y and Johanna Ivaska 1,2,* 1 Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; james.conway@utu.fi (J.R.W.C.); elisa.narva@utu.fi (E.N.); maria.taskinen@utu.fi (M.E.T.) 2 Department of Biochemistry, University of Turku, 20520 Turku, Finland * Correspondence: Johanna.ivaska@utu.fi These authors contributed equally to this work. y Received: 1 June 2020; Accepted: 1 July 2020; Published: 6 July 2020 Abstract: Microtubule-associated serine/threonine kinase-like (MASTL; Greatwall) is a well-characterized kinase, whose catalytic role has been extensively studied in relation to cell-cycle acceleration. Importantly, MASTL has been implicated to play a substantial role in cancer progression and subsequent studies have shown that MASTL is a significant regulator of the cellular actomyosin cytoskeleton. Several kinases have non-catalytic properties, which are essential or even sufficient for their functions. Likewise, MASTL functions have been attributed both to kinase-dependent phosphorylation of downstream substrates, but also to kinase-independent regulation of the actomyosin contractile machinery. In this review, we aimed to highlight the catalytic and non-catalytic roles of MASTL in proliferation, migration, and invasion. Further, we discussed the implications of this dual role for therapeutic design. Keywords: MASTL; actin; contractility; cell cycle; cancer; therapeutic targeting; kinase inhibitor 1. Introduction The serine/threonine kinase MASTL (microtubule-associated serine/threonine kinase-like; Greatwall) was first described in Drosophila melanogaster for the role it played in supporting cell-cycle progression [1]. Importantly, the MASTL gene is highly conserved from arthropods to vertebrates, speaking to the essential part that it plays in both development and tissue homeostasis [2,3] (Figure1A,B). In mammals, homozygous loss of MASTL is embryonically lethal at embryonic day 10.5, suggestive of pre-implantation lethality and highlighting the essential role of MASTL during development [4]. Cells 2020, 9, 1624; doi:10.3390/cells9071624 www.mdpi.com/journal/cells Cells 2020, 9, 1624 2 of 11 Cells 2020, 9, 1624 2 of 11 Figure 1. Microtubule-associated serine/threonine kinase-like MASTL structure and expression in Figure 1. Microtubule-associated serine/threonine kinase-like MASTL structure and expression in normal tissue and cancer. (A) Schematic of the human MASTL gene showing the catalytic domain (green),normal tissue along withand cancer. the sites (A of) kinase-inactivatingSchematic of the human (G44S) MASTL and clinically gene showing relevant the (E167D) catalytic mutations. domain In(green), line with along Hermida, with the D. sites et al.of kinase-inactivatin (2020), the commong (G44S) C- and and N-terminal clinically re lobeslevant (purple (E167D)/pink), mutations. cryptic C-lobeIn line (orange),with Hermida, AGCN-terminal D. et al. (2020), tail (blue), the common and the C- non-conserved and N-terminal middle lobes region (purple/pink), (NCMR) (white) cryptic are C- annotated.lobe (orange), The AGC site of N-terminal the V450 cancer-relevant tail (blue), and truncation the non-conserved is also indicated. middle For region further (NCMR) structural (white) details, are pleaseannotated. refer The to [5 ].site (B )of MASTL the V450 RNA cancer-relevant expression in normaltruncation tissue is [also6] (URL: indicated. http:// www.proteinatlas.orgFor further structural). Thedetails, organs please written refer with boldto [5] text. are(B provided) MASTL as illustrationsRNA expression (illustrations in normal provided tissue by Servier [6]Medical (URL: Arthttp://www.proteinatlas.org). under a Creative Commons The license, organs URL: written https: //withsmart.servier.com bold text are). Theprovided organs as (thyroid illustrations gland, ovary,(illustrations liver, colon, provided breast, by and Servier lung) written Medical in pinkArt textunder are wherea Creative high MASTL Commons expression license, has URL: been shownhttps://smart.servier.com). to correlate with poor The cancer organs prognosis (thyroid (or gland, where ovary, MASTL liver, has colon, been breast, associated and lung) with cancer).written in pink text are where high MASTL expression has been shown to correlate with poor cancer prognosis The(or where best-known MASTL roles has been forMASTL associated are with through cancer). kinase-dependent regulation of mitosis and meiosis, but several kinase-independent functions for MASTL during migration, adhesion, and invasion have recentlyThe been best-known described roles (Figure for2 ).MASTL Many kinases are through have important kinase-dependent functions independentregulation of of mitosis their kinase and domains,meiosis, but including several sca kinase-independentffolding, subcellular targeting,functions andfor directMASTL or indirectduring DNAmigration, binding adhesion, as a cofactor and forinvasion transcription, have recently along withbeen allosteric described and (Figur competitivee 2). Many roles forkinases other enzymeshave important [7]. For functions example, theindependent primary phosphorylation of their kinase domains, substrate forincluding focal adhesion scaffolding, kinase subcellular seems to betargeting, itself, where and direct many ofor itsindirect functions DNA are binding attributed as a tocofactor its ability for transcriptio to scaffold andn, along recruit with adhesion allosteric and and signaling competitive components. roles for Similarly,other enzymes many members[7]. For example, of the cyclin the familyprimary have phos beenphorylation recorded to substrate have kinase-independent for focal adhesion functions kinase inseems transcriptional to be itself, regulationwhere many [8]. of This its functions suggests thatare attributed many kinases to its may ability in fact to scaffold sit within and far recruit more complexadhesion regulatoryand signaling networks, components. working Similarly, beyond post-translational many members regulationof the cyclin of substrates. family have Here been we willrecorded discuss to recenthave kinase-independent studies that support functions a role for MASTLin transcriptional independent regulation of its kinase [8]. This activity, suggests outlining that themany dual kinases functionalities may in fact and sit attempting within far more to delineate complex the regulatory kinase-dependent networks, and working -independent beyond rolespost- duringtranslational cancer regulation progression. of substrates. Here we will discuss recent studies that support a role for MASTL independent of its kinase activity, outlining the dual functionalities and attempting to delineate the kinase-dependent and -independent roles during cancer progression. Cells 2020, 9, 1624 3 of 11 Cells 2020, 9, 1624 3 of 11 Figure 2. Illustration of known MASTL functions. The divisions between kinase-dependent and Figure 2. Illustration of known MASTL functions. The divisions between kinase-dependent and - -independent functions are suggestive and need to be studied further. independent functions are suggestive and need to be studied further. 2. MASTL in Cancer 2. MASTL in Cancer Cancer is responsible for the highest disease burden globally [9], and MASTL is implicated as a poorCancer prognostic is responsible factor for in the several highest of thedisease most bur lethalden globally cancer subtypes, [9], and MASTL including is implicated breast [10 ,as11 ],a gastricpoor prognostic [12], colon factor [13], in liver, several non-small-cell of the most lung lethal cancer cancer (NSCLC), subtypes, and including ovarian breast (Figure [10,11],3). The gastric roles of[12], MASTL colon in[13], cancer liver, are non-small-cell many and various, lung cancer where (NSCLC), multiple and studies ovarian have (Figure reported 3). that The silencing roles of decreasesMASTL in cell cancer proliferation, are many migration,and various, and where invasion, multiple while studies overexpression have reported can enhancethat silencing these propertiesdecreases cell (Figure proliferation,3A). Furthermore, migration, MASTL and in hasvasion, recently while been overexpression shown to inhibit can cellenhance spreading these andproperties attachment (Figure to the3A). extracellular Furthermore, matrix MASTL (ECM) has re [14cently], modify been cell–cell shown to contacts inhibit [cell14,15 spreading], and reduce and cell–cellattachment contact to the inhibition extracellular [15,16 ma]. Importantly,trix (ECM) [14], genetic modify ablation cell–cell of MASTL contacts has [14,15], a significant and reduce therapeutic cell– ecellffect contact in vivo inhibition [11,13,15 –[15,16].17], and Importantly, this provides genetic a solid ablation basis for of further MASTL therapeutic has a significant investigation. therapeutic effect in vivo [11,13,15–17], and this provides a solid basis for further therapeutic investigation. Figure 3. MASTL in cancer. (A) Literature describing MASTL function in various cancer types. The functional experiments (MASTL WT: overexpression of the wild type, MASTL K72M: overexpression Cells 2020, 9, 1624 3 of 11 Figure 2. Illustration of known MASTL functions. The divisions between kinase-dependent and - independent functions are suggestive and need to be studied further. 2. MASTL in Cancer Cancer is responsible for the highest disease burden globally
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