A Closer Look at JAK/STAT Signaling Pathway Emira Bousoik Chapman University

Chapman University Chapman University Digital Commons Pharmacy Faculty Articles and Research School of Pharmacy 7-31-2018 “Do We Know Jack” About JAK? A Closer Look at JAK/STAT Signaling Pathway Emira Bousoik Chapman University Hamidreza Montazeri Aliabadi Chapman University, [email protected] Follow this and additional works at: https://digitalcommons.chapman.edu/pharmacy_articles Part of the Amino Acids, Peptides, and Proteins Commons, Cancer Biology Commons, Cell Anatomy Commons, Cell Biology Commons, Enzymes and Coenzymes Commons, Oncology Commons, and the Other Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Bousoik E, Montazeri Aliabadi H. “Do we know jack” about JAK? A closer look at JAK/STAT signaling pathway. Front. Oncol. 2018;8:287. doi: 10.3389/fonc.2018.00287 This Article is brought to you for free and open access by the School of Pharmacy at Chapman University Digital Commons. It has been accepted for inclusion in Pharmacy Faculty Articles and Research by an authorized administrator of Chapman University Digital Commons. For more information, please contact [email protected]. “Do We Know Jack” About JAK? A Closer Look at JAK/STAT Signaling Pathway Comments This article was originally published in Frontiers in Oncology, volume 8, in 2018. DOI: 10.3389/ fonc.2018.00287 Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 License. Copyright The uthora s This article is available at Chapman University Digital Commons: https://digitalcommons.chapman.edu/pharmacy_articles/590 REVIEW published: 31 July 2018 doi: 10.3389/fonc.2018.00287 “Do We Know Jack” About JAK? A Closer Look at JAK/STAT Signaling Pathway Emira Bousoik 1,2 and Hamidreza Montazeri Aliabadi 1* 1 Department of Biomedical and Pharmaceutical Sciences, Center for Targeted Drug Delivery, School of Pharmacy, Chapman University, Irvine, CA, United States, 2 School of Pharmacy, Omar Al-Mukhtar University, Dèrna, Libya Janus tyrosine kinase (JAK) family of proteins have been identified as crucial proteins in signal transduction initiated by a wide range of membrane receptors. Among the proteins in this family JAK2 has been associated with important downstream proteins, including signal transducers and activators of transcription (STATs), which in turn regulate the expression of a variety of proteins involved in induction or prevention of apoptosis. Therefore, the JAK/STAT signaling axis plays a major role in the proliferation and survival of different cancer cells, and may even be involved in resistance mechanisms against molecularly targeted drugs. Despite extensive research focused on the protein structure and mechanisms of activation of JAKs, and signal transduction through these proteins, their importance in cancer initiation and progression seem to be underestimated. This Edited by: manuscript is an attempt to highlight the role of JAK proteins in cancer biology, the Anna Rita Migliaccio, Icahn School of Medicine at Mount most recent developments in targeting JAKs, and the central role they play in intracellular Sinai, United States cross-talks with other signaling cascades. Reviewed by: Alessandro Malara, Keywords: janus tyrosine kinases (JAKs), signal transducers and activators of transcription (STATs), cancer, University of Pavia, Italy signaling pathways, proliferation, survival Francesca Palandri, Università degli Studi di Bologna, Italy *Correspondence: INTRODUCTION Hamidreza Montazeri Aliabadi [email protected] The fate of our cells is mainly decided by the intracellular signaling pathways that control mechanisms involved in phenotypical modifications. This crucial role becomes even more Specialty section: significant in cancer cells that rely upon a vast, complicated, and inter-connected network of This article was submitted to signaling pathways for their survival and proliferation. Signaling pathways are mostly activated Cancer Molecular Targets and through cell membrane receptors that are triggered by different ligands, which initiate the Therapeutics, mechanisms responsible for controlling phenotypical outcomes, e.g., proliferation, or apoptosis. a section of the journal For instance, Receptor tyrosine kinases (RTKs, including epidermal growth factor receptor or Frontiers in Oncology EGFR, and human epidermal growth factor receptor 2 or HER2) and cytokine receptors are Received: 09 June 2018 among the most important cell surface receptors that activate these signaling cascades. It is well- Accepted: 09 July 2018 established that cancer is a heterogeneous disease (1–5). In 2015, Sottoriva et al. proposed a “Big Published: 31 July 2018 Bang” model of tumor initiation in colorectal cancer that suggests after initial oncogenic mutation, Citation: future generations acquire further mutations, which are present in discrete populations of cells that Bousoik E and Montazeri Aliabadi H then expand as the tumor grows, leading to spatial heterogeneity (6). A similar and even more (2018) “Do We Know Jack” About JAK? A Closer Look at JAK/STAT diverse pattern has been reported for other types of cancer. Amir et al. studied two human acute Signaling Pathway. lymphoblastic leukemia samples with viSNE technology, and reported a large, irregular mass of Front. Oncol. 8:287. abnormal cells that were more different than similar (7). The sub-population of a sample with doi: 10.3389/fonc.2018.00287 intrinsic resistance to a therapeutic assault (due to different mutations in the target protein, and/or Frontiers in Oncology | www.frontiersin.org 1 July 2018 | Volume 8 | Article 287 Bousoik and Montazeri Aliabadi JAK/STAT Signaling Pathway reliance on an alternative mechanism) would survive and strategy. Figure 1 summarizes the intracellular signaling cascades outgrow other cells due to the selection pressure, and promotes involving activation of JAK proteins. relapse after therapy, which results in abundance of cells that were once minority (8). This “Darwinian clone selection” has been well-documented in different types of cancer cells in respond to A BRIEF HISTORY a variety of molecularly targeted drugs (9). This inter- and intra- tumor heterogeneity means that each cancer cell potentially has JAK/STAT signaling cascade is among the highly conserved access to a wide variety of mechanisms to arrive at the same metazoan pathways observed in a wide range of species (23), phenotypical outcome. which is involved in an array of cytokines and growth factors In addition to the diversity of the signaling pathways, (22). The “story” of this silencing pathway has been previously which provides ample opportunities for cancer cells to “switch” reviewed in detail (24), where the authors track the origins pathways as a response to molecularly targeted drugs, and of the discovery to 1950s and interferons. Our knowledge of to make the matters even more complicated, these pathways existence of JAK/STAT pathway, however, is <3 decades old. are also not completely independent, and are engaged in JAK1and JAK2 were identified in 1989, and the first member signaling cascade “cross-talk.” Recent findings have revealed off JAK family of proteins was cloned and synthesized in 1990 extensive interactions between traditionally categorized cascades, (25). The gene was named Tyk2, and attracted attention due to which has blurred the line between parallel pathways. Many a “kinase-like” domain next to the well-known and conserved of the effector proteins seem to multi-task and be involved in protein tyrosine kinase domain (26). JAK name was taken from different mechanisms. Activation of HER2, a tyrosine kinase two-faced Roman God of doorways, Janus because the way membrane receptor specifically expressed in breast cancer that JAK possesses two near-identical phosphate-transferring cell membrane, triggers phosphorylation of RAF and Ras, domains: One domain exhibits the kinase activity while the other which results in over-expression of Bcl-2 family proteins (10). negatively regulates the kinase activity of the first (24, 27). Wilks Another widely inter-connected protein is MUC1, which is over- et al. cloned and published the complementary DNA sequence expressed in different types of carcinomas and is correlated for JAK2 in 1992, and demonstrated the same kinase/“pseudo- with higher risk of metastasis and poor survival rate (10). kinase” sections in the protein structure (28). In 1992 Shuai et MUC1 interacts with several cytoplasmic proteins and Ras- al reported sequencing cDNA clones that were later called signal Raf-MEK-ERK signaling pathway (11), STAT3 (mediated by transducer and activator of transcription (STAT1; a and b) and Src) (12), and proteins known to be activated by EGFR (13). STAT2 (29, 30). Later on, graduate students in Darnell lab cloned Studies also indicate that crosstalk among signaling pathways STAT3 and 4 from a lymphocyte cDNA library, establishing their contributes to a deregulation of PI3K–PTEN signaling that can membership in STATs family, and demonstrating that IL6 and lead to tumorigenesis (14). This could at least partially explain EGF triggered phosphorylation of STAT3 (31, 32). The gene the growing number of preclinical data that indicate a failure encoding STAT5 (initially named mammary gland factor; MGF) to induce apoptosis despite effective inhibition of PI3K-Akt was cloned and sequenced in Groner’s lab in 1994 (33). It was components (15, 16). not until twenty first century that initial reports were published Janus tyrosine kinase (JAK) and signal transducers and to link mutations in JAKs and STATs (resulting in persistent

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