Signal transducer and activator of transcription 5 (STAT5) refers to two highly relatedproteins,STAT5A andSTAT5B, which are part of the seven-memberedSTAT family of proteins. Though STAT5A and STAT5B are encoded by separategenes, the proteins are 90% identical at theamino acid level.[1] STAT5 proteins are involved incytosolicsignalling and in mediating theexpression of specific genes.[2] Aberrant STAT5 activity has been shown to be closely connected to a wide range of humancancers,[3] and silencing this aberrant activity is an area of active research inmedicinal chemistry.[4]
In order to be functional, STAT5 proteins must first be activated. This activation is carried out bykinases associated withtransmembrane receptors:[3]
Ligands binding to these transmembrane receptors on the outside of the cell activate the kinases;
The stimulated kinases add aphosphate group to a specifictyrosine residue on the receptor;
STAT5 then binds to these phosphorylated-tyrosines using theirSH2 domain(STAT domains illustrated below);
The bound STAT5 is then phosphorylated by the kinase, the phosphorylation occurring at particular tyrosine residues on theC-terminus of the protein;
Phosphorylation causes STAT5 to dissociate from the receptor;
The phosphorylated STAT5 finally goes on to form eitherhomodimers, STAT5-STAT5, orheterodimers, STAT5-STATX, with other STAT proteins. The SH2 domains of the STAT5 proteins are once again used for this dimerization. STAT5 can also form homo-tetramers, usually in concert with the histone methyltransferaseEZH2, and act as a transcriptional repressor.[5]
STAT5 activation.
In the activation pathway illustrated to the left, the ligand involved is acytokine and the specific kinase taking part in activation isJAK. The dimerized STAT5 represents the active form of the protein, which is ready fortranslocation into thenucleus.
Once in the nucleus, the dimers bind to STAT5response elements, inducingtranscription of specific sets of genes. Upregulation of gene expression by STAT5 dimers has been observed for genes dealing with:[2]
Activated STAT5 dimers are, however, short-lived and the dimers are made to undergo rapid deactivation. Deactivation may be carried out by a direct pathway, removing the phosphate groups usingphosphatases likePIAS or SHP-2 for example, or by an indirect pathway, which involves reducing cytokine signalling.[6]
STAT5 has been found to be constitutively phosphorylated in cancer cells,[4] implying that the protein is always present in its active form. This constant activation is brought about either bymutations or by aberrant expressions of cell signalling, resulting in poor regulation, or complete lack of control, of the activation oftranscription for genes influenced by STAT5. This leads to constant and increased expression of these genes. For example, mutations may lead to increased expression of anti-apoptotic genes, the products of which actively prevent cell death. The constant presence of these products preserves the cell in spite of it having become cancerous, causing the cell to eventually becomemalignant.
Attempts at treatment for cancer cells with constitutively phosphorylated STAT5 have included both indirect and direct inhibition of STAT5 activity. While more medicinal work has been done in indirect inhibition, this approach can lead to increased toxicity in cells and can also result in non-specific effects, both of which are better handled by direct inhibition.[4]
Indirect inhibition targets kinases associated with STAT5, or targets proteases that carry out terminal truncation of proteins. Different inhibitors have been designed to target different kinases:
Inhibition ofJAK2 is carried out by the drugCYT387, which was successful in preclinical trials and is currently undergoing clinical trials.[9]
Domains of STAT proteins
Direct inhibition of STAT5 activity makes use ofsmall molecule inhibitors that prevent STAT5 from properly binding to DNA or prevent proper dimerization. The inhibiting of DNA binding utilizesRNA interference,[10] antisense oligodeoxynucleotide,[10] andshort hairpin RNA.[11] The inhibition of proper dimerization, on the other hand, is brought about by the use of small molecules that target the SH2 domain. Recent work on drug development in the latter field have proved particularly effective.[12]
^Grimley PM, Dong F, Rui H (June 1999). "Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation".Cytokine Growth Factor Rev.10 (2):131–57.doi:10.1016/S1359-6101(99)00011-8.PMID10743504.
^abcCumaraswamy AA, Todic A, Resetca D, Minden MD, Gunning PT (January 2012). "Inhibitors of Stat5 protein signalling".MedChemComm.3 (1):22–27.doi:10.1039/C1MD00175B.
^Shuai K, Halpern J, ten Hoeve J, Rao X, Sawyers CL (July 1996). "Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia".Oncogene.13 (2):247–54.PMID8710363.
^Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (May 1996). "Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells".Nat. Med.2 (5):561–6.doi:10.1038/nm0596-561.PMID8616716.S2CID36102747.
