Involvement of STAT5 in Oncogenesis
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biomedicines Review Involvement of STAT5 in Oncogenesis Clarissa Esmeralda Halim 1, Shuo Deng 1, Mei Shan Ong 1 and Celestial T. Yap 1,2,3,* 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; [email protected] (C.E.H.); [email protected] (S.D.); [email protected] (M.S.O.) 2 Medical Science Cluster, Cancer Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore 3 National University Cancer Institute, National University Health System, Singapore 119074, Singapore * Correspondence: [email protected]; Tel.: +65-6516-3294 Received: 14 July 2020; Accepted: 26 August 2020; Published: 28 August 2020 Abstract: Signal transducer and activator of transcription (STAT) proteins, and in particular STAT3, have been established as heavily implicated in cancer. Recently, the involvement of STAT5 signalling in the pathology of cancer has been shown to be of increasing importance. STAT5 plays a crucial role in the development of the mammary gland and the homeostasis of the immune system. However, in various cancers, aberrant STAT5 signalling promotes the expression of target genes, such as cyclin D, Bcl-2 and MMP-2, that result in increased cell proliferation, survival and metastasis. To target constitutive STAT5 signalling in cancers, there are several STAT5 inhibitors that can prevent STAT5 phosphorylation, dimerisation, or its transcriptional activity. Tyrosine kinase inhibitors (TKIs) that target molecules upstream of STAT5 could also be utilised. Consequently, since STAT5 contributes to tumour aggressiveness and cancer progression, inhibiting STAT5 constitutive activation in cancers that rely on its signalling makes for a promising targeted treatment option. Keywords: STAT5; cancer; metastasis; proliferation; angiogenesis 1. Introduction The signal transducer and activator of transcription (STAT) family is comprised of seven members, namely STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6 [1–4]. These proteins are transcription factors that are activated upon phosphorylation by Janus kinases (JAKs) in response to cytokine signalling [1,5]. Upon the binding of a cytokine to its receptor, the activated receptor on the cell surface membrane will induce the phosphorylation of JAKs, which will recruit the corresponding STAT protein to activate it by phosphorylation [6–9]. Full activation of the phosphorylated STAT proteins only occurs when they either homo- or heterodimerise, upon which they could form stable tetramers that translocate to the nucleus to bind more efficiently to the interferon gamma activated sites (GAS) of the promoters of STATs-regulated genes [5,7,10–13]. Apart from its activation, the STAT signalling pathway could also be negatively regulated by other proteins, such as phosphatases, the suppressors of cytokine signalling (SOCS) and protein inhibitors of activated STAT (PIAS), which dephosphorylate activated JAKs and STATs, prevent STATs activation by JAKs, and bind activated STATs to GAS sites, respectively [5,14–16]. Several STAT proteins have been found to be linked to the cancer pathology, for example, constitutively activated STAT1, STAT3 and STAT5 have been found in breast, lung, prostate and pancreatic cancers, and other haematological malignancies [17–22]. The upregulation of these STATs signalling pathways promotes tumour growth and survival due to the inhibition of apoptosis, increased cell proliferation, migration and invasion, and dysregulated immune surveillance [17,23–25]. Of these three STAT proteins that are most implicated in cancer, many studies have been focused on the roles of Biomedicines 2020, 8, 316; doi:10.3390/biomedicines8090316 www.mdpi.com/journal/biomedicines Biomedicines 2020, 8, x FOR PEER REVIEW 2 of 20 Biomedicines 2020, 8, 316 2 of 20 on the roles of STAT3 in tumour development [17,26–28]. However, it was only more recently that STAT5 has been shown to play a major role in the tumour progression of several cancers as well. STAT3 in tumour development [17,26–28]. However, it was only more recently that STAT5 has been Therefore, we will be focusing on the implications of constitutive STAT5 signalling in various cancers, shown to play a major role in the tumour progression of several cancers as well. Therefore, we will as well as the therapies available to target it. be focusing on the implications of constitutive STAT5 signalling in various cancers, as well as the therapies available to target it. 2. STAT5 and Its Isoforms 2. STAT5STAT5 and was Its originally Isoforms discovered as a transcription factor of the β-casein gene in lactating mammarySTAT5 cells was and originally was called discovered the mammary as a transcriptiongland factor (MGF) factor [29]. of the Theβ cloning-casein of gene MGF in indicated lactating thatmammary it belonged cells andto the was STAT called family the mammaryof proteins gland and was factor then (MGF) designated [29]. The as ST cloningAT5 [30]. of MGF It is indicateda protein ofthat 794 it belonged amino toacids, the STAT and familycould of be proteins activated and wasby thenprolactin designated (PRL) as STAT5signalling [30]. Itthrough is a protein JAK2 of phosphorylation794 amino acids, andon its could Tyr694 be activatedresidue [29,30]. by prolactin (PRL) signalling through JAK2 phosphorylation on itsFurther Tyr694 molecular residue [29 ,studies30]. have elucidated that two clustered genes on chromosome 17 in humansFurther encode molecular for STAT5. studies The have two elucidatedgenes give that rise two to two clustered different genes isoforms, on chromosome STAT5a and 17 in STAT5b, humans whichencode have for STAT5. more than The two90% genespeptide give sequence rise to two identi difftyerent [31]. isoforms, STAT5a STAT5awas used and to STAT5b,denote the which original have STAT5more than discovered 90% peptide in PRL sequence signalling, identity while [31 STAT5b]. STAT5a is a was protein used with to denote 786 amino the original acids, and STAT5 is phosphorylateddiscovered in PRL on signalling, its Tyr699 whileresidu STAT5be in contrast is a protein to Tyr694 with in 786 STAT5a amino [31]. acids, Both and isoforms is phosphorylated share the sameon its functional Tyr699 residue domains in contrast arrangement, to Tyr694 as shown in STAT5a in Figure [31]. Both1, and isoforms have similar share structures. the same functional Since the twodomains isoforms arrangement, are highly assimilar, shown they in Figure have redund1, and haveant functions similar structures.in regulating Since genes the responsible two isoforms for someare highly cellular similar, processes, they have such redundant as cell proliferation functions inand regulating apoptosis genes [32]. responsibleHowever, due for someto structural cellular differencesprocesses, such on the as C-terminal cell proliferation regions, and they apoptosis also have [32 non-redundant]. However, due functi to structuralons. For example, differences STAT5a on the andC-terminal STAT5b regions, have been they found also haveto be non-redundantassociated with functions.genes modulating For example, neural STAT5a and T-cell and development, STAT5b have respectivelybeen found to[32]. be associated with genes modulating neural and T-cell development, respectively [32]. FigureFigure 1. 1. StructureStructure of of the the STAT5 STAT5 isoforms, isoforms, STAT5a STAT5a and STAT5b. 3. Roles of STAT5 in Physiology 3. Roles of STAT5 in Physiology The activation of STAT5 (Figure2) occurs when ligands responsible for this signalling pathway, The activation of STAT5 (Figure 2) occurs when ligands responsible for this signalling pathway, such as the cytokines interleukin-2 (IL-2) and IL-3, bind to their respective receptors, causing them to such as the cytokines interleukin-2 (IL-2) and IL-3, bind to their respective receptors, causing them to dimerise or multimerise, bringing JAKs into close proximity to transphosphorylate each other as well dimerise or multimerise, bringing JAKs into close proximity to transphosphorylate each other as well as the receptors [14,33–35]. This will recruit STAT5 to the receptors, and they will be phosphorylated on as the receptors [14,33–35]. This will recruit STAT5 to the receptors, and they will be phosphorylated their critical tyrosine residue by the activated JAKs [34,35]. Once they are phosphorylated, STAT5 will on their critical tyrosine residue by the activated JAKs [34,35]. Once they are phosphorylated, STAT5 dimerise with each other, where the SH2 domain of each STAT5 molecule will interact via the will dimerise with each other, where the SH2 domain of each STAT5 molecule will interact via the phospho-tyrosine (pY) residue of the other STAT5 [14,34,35]. The translocation of the fully activated phospho-tyrosine (pY) residue of the other STAT5 [14,34,35]. The translocation of the fully activated STAT5 dimer into the nucleus will then occur, whereby it will bind to GAS elements through its STAT5 dimer into the nucleus will then occur, whereby it will bind to GAS elements through its DNA-binding domain (DBD) [35,36]. Transcriptional regulation of STAT5 target genes, such as those DNA-binding domain (DBD) [35,36]. Transcriptional regulation of STAT5 target genes, such as those that promote cell proliferation, cyclin D and serine/threonine kinase Pim-1, as well as those involved that promote cell proliferation, cyclin D and serine/threonine kinase Pim-1, as well as those involved in apoptosis like Janus kinase-binding protein (JAB), could then be activated