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Human B-Cell Proliferation and Intracellular Signaling: Part 3

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Human B-Cell Proliferation and Intracellular Signaling: Part 3 1872 Diabetes Volume 64, June 2015 Andrew F. Stewart,1 Mehboob A. Hussain,2 Adolfo García-Ocaña,1 Rupangi C. Vasavada,1 Anil Bhushan,3 Ernesto Bernal-Mizrachi,4 and Rohit N. Kulkarni5 Human b-Cell Proliferation and Intracellular Signaling: Part 3 Diabetes 2015;64:1872–1885 | DOI: 10.2337/db14-1843 This is the third in a series of Perspectives on intracel- signaling pathways in rodent and human b-cells, with lular signaling pathways coupled to proliferation in pan- a specific focus on the links between b-cell proliferation creatic b-cells. We contrast the large knowledge base in and intracellular signaling pathways (1,2). We highlight rodent b-cells with the more limited human database. what is known in rodent b-cells and compare and contrast With the increasing incidence of type 1 diabetes and that to the current knowledge base in human b-cells. In- the recognition that type 2 diabetes is also due in part variably, the human b-cell section is very brief compared fi b to a de ciency of functioning -cells, there is great ur- with the rodent counterpart, reflecting the still primitive gency to identify therapeutic approaches to expand hu- state of our understanding of mitogenic signaling in hu- b man -cell numbers. Therapeutic approaches might man b-cells. To emphasize this difference, each figure is include stem cell differentiation, transdifferentiation, or divided into two panels, one summarizing rodent b-cell expansion of cadaver islets or residual endogenous signaling and one for human b-cells. Our intended audi- b-cells. In these Perspectives, we focus on b-cell ence includes trainees in b-cell regeneration as well as proliferation. Past Perspectives reviewed fundamental cell cycle regulation and its upstream regulation by experts in a given pathway who wish to refresh their insulin/IGF signaling via phosphatidylinositol-3 kinase/ knowledge regarding other pathways related to b-cell pro- mammalian target of rapamycin signaling, glucose, gly- liferation. We believe that knowledge of b-cell signaling fi cogen synthase kinase-3 and liver kinase B1, protein lags signi cantly behind other areas in b-cell biology, that kinase Cz, calcium-calcineurin–nuclear factor of acti- understanding why adult human b-cells are so recalcitrant vated T cells, epidermal growth factor/platelet-derived to induction of proliferation is critically important, and PERSPECTIVES IN DIABETES growth factor family members, Wnt/b-catenin, leptin, that deepening knowledge in this area will reveal novel and estrogen and progesterone. Here, we emphasize approaches and targets for the therapeutic induction of Janus kinase/signal transducers and activators of tran- human b-cell expansion. scription, Ras/Raf/extracellular signal–related kinase, Readers are urged to refer to the prior two Perspectives for cadherins and integrins, G-protein–coupled receptors, additional background and cross-correlation (1,2). These have and transforming growth factor b signaling. We hope covered the fundamentals of cell cycle control in the b-cell, these three Perspectives will serve to introduce these and several key mitogenic b-cell signaling pathways: insulin/ pathways to new researchers and will encourage addi- IGF/insulin receptor substrate (IRS)/phosphatidylinositol-3 tional investigators to focus on understanding how to kinase (PI3K)/Akt/glycogen synthase kinase-3b (GSK3b)/ harness key intracellular signaling pathways for thera- mammalian target of rapamycin (mTOR) signaling, protein peutic human b-cell regeneration for diabetes. kinase Cz (PKCz) signaling, glucose and nutrient signaling via AMPK/liver kinase B, carbohydrate response element– This is the third in a series of Perspectives in Diabetes binding protein (ChREB) and cMyc, calcium-calcineurin– reviewing and emphasizing the importance of intracellular nuclear factor of activated T cells signaling, epidermal 1Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Corresponding author: Andrew F. Stewart, [email protected], or Rohit Sinai, New York, NY N. Kulkarni, [email protected]. 2 Departments of Medicine and Pediatrics, Johns Hopkins School of Medicine, Received 2 December 2014 and accepted 16 January 2015. Baltimore, MD © 2015 by the American Diabetes Association. Readers may use this article as 3Diabetes Center, University of California, San Francisco, San Francisco, CA long as the work is properly cited, the use is educational and not for profit, and 4Division of Metabolism, Endocrinology & Diabetes, University of Michigan, the work is not altered. Ann Arbor, MI, and VA Ann Arbor Healthcare System, Ann Arbor, MI 5Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA diabetes.diabetesjournals.org Stewart and Associates 1873 growth factor (EGF) and platelet-derived growth factor can activate not only “their own pathway,” but also (PDGF) signaling, Wnt/b-catenin signaling and leptin sig- can cross talk with members of the Ras/Raf/MAPK and naling, estrogen and progesterone signaling, and, a brief PI3K-Akt/protein kinase B (PKB)-mTOR pathways (Fig. introduction to lactogenic signaling. Here, we focus in 1A). This happens via adapter molecules such as Grb2, greater detail on cytokine/Janus kinase/signal trans- Shp2, SHC, SH2B1, IRS2, c-Src, SOS, and others (10– ducers and activators of transcription (JAK-STAT) signal- 15). Thus, a response initiated by a cytokine or hormone ing, Ras/Raf/mitogen-activated protein kinase (MAPK) receptor in the GHR/PRLR family may be driven or en- signaling, cell-cell signaling via cadherins and integrins, hanced by a non–JAK-STAT signaling pathway. Further, G-protein–coupled receptor (GPCR) signaling, and trans- unphosphorylated STATs can also access the nucleus and forming growth factor b (TGFb) superfamily signaling. bind to promoters, in some cases in a competitive manner by inhibiting phospho-STAT DNA binding (3–5). For CYTOKINE AND HORMONE SIGNALING THROUGH unphosphorylated STAT5, tetramers can form and recruit JAK-STAT PATHWAYS Ezh2 (3–5), a component of the polycomb repressive com- Canonical JAK-STAT Signaling plex that regulates, for example, cell cycle inhibitors such b-Cells are exposed to some 60 cytokines (e.g., interleukin as p16INK4. In yet another variation, some STATs can be [IL]-1, IL-2, and IL-6) and hormones (e.g., growth hormone methylated by lysine/histone methylases, such as SET9, [GH], prolactin [PRL], placentallactogens[PLs],leptinand and thereby serve to recruit other transcription complex erythropoietin [EPO]) that signal through JAK-STAT path- members to select promoters (3–5). And in still another ways. Connecting the dimeric or multimeric cell surface example, JAK2 has been reported to link the GHR to the receptors for these molecules to downstream events is a fam- IGF-1 receptor and thereby synergizes to enhance the ily of intracellular signaling molecules that exert positive and effects of GH signaling (16). negative feedback signals to activate signaling and then ter- minate it (reviewed in detail in references [3–9]). Rodent b-Cells In a relevant example of JAK-STAT signaling (Fig. 1A) As reviewed previously (1), PRL/PL have been reported to (3–7,10), under basal conditions, the PRL receptor (PRLR) drive b-cell proliferation in pregnancy via a canonical or GH receptor (GHR) homodimers or heterodimers on the JAK2-STAT5 pathway. This requires the PRLR, as the cell surface are coupled to two JAK2 molecules; cytoplasmic b-cell PRLR knockout (KO) mouse develops b-cell hypo- STAT5 homodimers are loosely bound to the receptor from plasia and gestational diabetes mellitus (17–19). JAK2 is a reservoir in the cytoplasm. GH binding to GHR or PRL to present, and STATs 5a and 5b have been shown to be PRLR rearranges intracellular receptor alignment, activating phosphorylated and to translocate to the nucleus in asso- the JAK2 pair that then cross-phosphorylate one another as ciation with cell cycle activation via cyclin D2, forkhead well as the GHR or PRLR, which then strongly recruits box protein M1 (FoxM1), and other G1/S control mole- STAT5 dimers to the GHR or PRLR. JAK2 then phosphor- cules (20,21). In mice, conditional loss of both STAT5a/b ylates STAT5 homodimers, which causes their disassociation using a pancreatic and duodenal homeobox 1 (Pdx1)-Cre from the GHR or PRLR, permitting STAT5 translocation to (22) or transgenic dominant-negative STAT5 expression the nucleus. Here, phospho-STAT5 homodimers bind (23) results in mild reductions in b-cell proliferation to gamma-interferon–activated sequences (the canonical and function. As also described previously (1), in two STAT response elements) in many promoters, thus initi- parallel cascades, PRLR-JAK2-STAT5 transcriptionally ating transcriptional activation of STAT5 target genes, drives a Bcl6/menin–p18INK4/p27CIP pathway (24), as exemplified by IGF-1 for GH signaling or cell cycle mole- well as serotoninergic pathway via induction of trypto- cules for PRL signaling. phan hydroxylases 1 and 2 (Tph1/2), with induction of proliferation via the serotonin receptor, 5HTR2b (25,26). Terminating JAK-STAT Signaling As a footnote, rodent b-cells contain STAT3, but its con- Activated STATs also trigger suppressors of cytokine ditional loss has no effect on b-cells (27). signaling (SOCS), cytokine-inducible SH2 domain-containing Noncanonical JAK-STAT events occur in b-cells as well. proteins (CISH), and protein inhibitors of activated STAT For example, the cytosolic carboxy-terminal fragment of (PIAS) transcription (Fig. 1A), which act in a classical neg- islet cell antigen 512 (ICA-512-CCF) is released from the ative feedback manner to terminate upstream signals b-cell membrane by insulin secretion and transits to the (8,9). SOCS and CISH accomplish this by competing nucleus, where it enhances STAT5-mediated insulin secre- with JAK-STAT interactions, by blocking the kinase activ- tion and D-cyclin transcription (28). As another nonca- ity of JAK proteins, and by serving as E3 ligase complexes nonical example, the adaptor protein SH2B1, which is that target JAKs and their receptors for ubiquitination known to interact with JAK2, enhances insulin, IGF1, and proteosomal degradation.
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