International Journal of Molecular Sciences Review Role of Receptor Protein Tyrosine Phosphatases (RPTPs) in Insulin Signaling and Secretion Julio Sevillano , María Gracia Sánchez-Alonso , Javier Pizarro-Delgado and María del Pilar Ramos-Álvarez * Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925 Alcorcón, Madrid, Spain; [email protected] (J.S.); [email protected] (M.G.S.-A.); [email protected] (J.P.-D.) * Correspondence: [email protected] Abstract: Changes in lifestyle in developed countries have triggered the prevalence of obesity and type 2 diabetes mellitus (T2DM) in the latest years. Consequently, these metabolic diseases associated to insulin resistance, and the morbidity associated with them, accounts for enormous costs for the health systems. The best way to face this problem is to identify potential therapeutic targets and/or early biomarkers to help in the treatment and in the early detection. In the insulin receptor signaling cascade, the activities of protein tyrosine kinases and phosphatases are coordinated, thus, protein tyrosine kinases amplify the insulin signaling response, whereas phosphatases are required for the regulation of the rate and duration of that response. The focus of this review is to summarize the impact of transmembrane receptor protein tyrosine phosphatase (RPTPs) in the insulin signaling cascade and secretion, and their implication in metabolic diseases such as obesity and T2DM. Citation: Sevillano, J.; Sánchez- Keywords: receptor protein tyrosine phosphatases (RPTP); insulin signaling; insulin secretion; T2DM Alonso, M.G.; Pizarro-Delgado, J.; Ramos-Álvarez, M.d.P. Role of Receptor Protein Tyrosine Phosphatases (RPTPs) in Insulin 1. Introduction Signaling and Secretion. Int. J. Mol. 1.1. Metabolic Diseases Associated with Insulin Resistance and Chronic Low-Grade Inflammation Sci. 2021, 22, 5812. https://doi.org/ Type 2 diabetes mellitus (T2DM) and obesity are two major medical challenges of 10.3390/ijms22115812 the 21st century with increasing prevalence during the last decades, reaching pandemic Academic Editor: Jean-François Tanti proportions [1]. Both metabolic diseases are associated to insulin resistance, and although only a subset of obese people develops T2DM, obesity is a major risk factor for T2DM, and Received: 1 May 2021 rates of T2DM prevalence have paralleled those of obesity. Consequently, these metabolic Accepted: 24 May 2021 diseases, and the morbidity associated with them, accounts for enormous costs for the Published: 28 May 2021 health systems. Insulin resistance is a condition in which tissues are unable to respond to normal Publisher’s Note: MDPI stays neutral plasma insulin level, with tissue-specific functional consequences. The integrated physiol- with regard to jurisdictional claims in ogy of insulin resistance owes to defective insulin action at target cells. Thus, the research published maps and institutional affil- on insulin resistance has usually been focused on the critical nodes of the signaling path- iations. way (insulin receptor, insulin receptor substrates (IRS) proteins, protein kinase B (AKT)) described with detail in Figure1. Both obesity and T2DM [2] are also associated with the development of a chronic low-grade inflammation in adipose tissue, with local production of proinflammatory Copyright: © 2021 by the authors. cytokines [3], such as tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) [4] that Licensee MDPI, Basel, Switzerland. can interfere with insulin receptor signaling (see Figure1) and cause insulin resistance [ 5]. This article is an open access article Many of these obesity/T2DM-generated inflammatory signals converge to activate serine distributed under the terms and kinases promoting Ser phosphorylation of IRS1 (pSerIRS1), that directly interferes with conditions of the Creative Commons insulin action in adipose tissue both in pathological [6] and physiological conditions [7]. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 5812. https://doi.org/10.3390/ijms22115812 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 5812 2 of 11 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 12 Figure 1. Insulin signaling cascade.Figure 1. Insulin signaling cascade. Insulin signalingInsulin begins signaling with its begins binding with to its the binding cell surface to the cellinsulin surface receptor insulin (IR), receptor a (IR), a het- heterotetrametricerotetrametric protein (two protein α extracellular (two α extracellular subunits and subunits two transmembrane and two transmembrane β-subu- β-subunits) nits) which is whicha tyrosine is a tyrosinekinase [8]. kinase The binding [8]. The of binding insulin of to insulin its receptor to its receptorleads to leadsthe acti- to the activation vation of IR tyrosineof IR tyrosine kinase; kinase;the receptor the receptor is autophosphorylated is autophosphorylated in key tyrosine in key (pY) tyrosine resi- (pY) residues dues of the β-subunits,of the β-subunits, which function which as function a docking as asite docking for tyrosine site for phosphorylated tyrosine phosphorylated adap- adaptor tor proteins suchproteins as insulin such as receptor insulin receptorsubstrates substrates 1 and 2 (IRS-1/2) 1 and 2 (IRS-1/2) that are thatsubsequently are subsequently phos- phosphorylated.phorylated. The recruitment The recruitment of phosphotyrosine of phosphotyrosine IRS-1/2 to IRS-1/2IR leads toto IRthe leads activation to the activation of of the two majorthe downstream two major downstream pathways, the pathways, phosphatidylinos the phosphatidylinositol-3-kinaseitol-3-kinase (PI3K) and the (PI 3K) and the mitogen-activatedmitogen-activated protein kinase protein (MAPK) kinase pathway (MAPK) initiated pathway by growth initiated factor by growth receptor factor receptor bound proteinbound 2 (GRB2) protein and 2the (GRB2) Src homology and the Srcand homology collagen (SHC). and collagen First, activation (SHC). First, of the activation of the PI3K leads to PI3-phosphoinositide-dependent3K leads to 3-phosphoinositide-dependent protein kinase protein 1 (PDK1)-dependent kinase 1 (PDK1)-dependent phos- phospho- phorylation andrylation the subsequent and the subsequent activation activation of the protein of the kinase protein B (PKB kinase or B AKT), (PKB orwhich AKT), in which in turn turn phosphorylatesphosphorylates various key various downstream key downstream effectors effectors involved involved in the metabolic in the metabolic effects effects of the of the insulin,insulin, including including glycogen glycogen synthase synthase kinase kinase (GSK)-3, (GSK)-3, Forkhead Forkhead box box protein protein O O (FOXO), and (FOXO), and mechanisticmechanistic target target of rapamycin (mTOR).(mTOR). Secondly,Secondly, activation activation of of the the MAPK MAPK cascade, which cascade, whichincludes includes rat rat sarcoma sarcoma (RAS), (RAS), rapidly rapidly accelerated accelerated fibrosarcoma fibrosarcoma (RAF), (RAF), mitogen-activated mi- togen-activatedprotein/extracellular protein/extracellular signal-regulated signal-regulated kinase kinase (MEK1/2), (MEK1/2), and and extracellular extracellular signal-regulated kinase (ERK1/2), plays a critical role for mitogenic effects of insulin, including prolif- signal-regulated kinase (ERK1/2), plays a critical role for mitogenic effects of insulin, in- eration, differentiation and survival [9]. Insulin signaling is negatively regulated by a cluding proliferation, differentiation and survival [9]. Insulin signaling is negatively reg- number of mechanisms, such as a) the binding of GRB10 to the kinase domain of IR; b) ulated by a number of mechanisms, such as a) the binding of GRB10 to the kinase domain the serine/theonine phosphorylation (pS) of IRS1 by various serine/threonine kinases of IR; b) the serine/theonine phosphorylation (pS) of IRS1 by various serine/threonine ki- (STK), including IκB kinase β (IKKβ), c-Jun N-terminal kinase (JNK), S6K and mTOR3 [6]; nases (STK), including IκB kinase β (IKKβ), c-Jun N-terminal kinase (JNK), S6K and c) dephosphorylation of IR and IRS1/2 by protein tyrosine phosphatases (PTPs) such as mTOR3 [6]; c) dephosphorylation of IR and IRS1/2 by protein tyrosine phosphatases phosphatase-1B (PTP-1B) [10], and d) dephosphorylation of phosphatidylinositol 3,4,5- (PTPs) such as phosphatase-1B (PTP-1B) [10], and d) dephosphorylation of phosphatidyl- trisphosphate (PIP3) into phosphatidylinositol 4,5-bisphosphate (PIP2) by the phosphatase inositol 3,4,5-trisphosphate (PIP3) into phosphatidylinositol 4,5-bisphosphate (PIP2) by and tensin homolog (PTEN). the phosphatase and tensin homolog (PTEN). 1.2. Role of Protein Tyrosine Kinases and Protein Tyrosine Phosphatases Antagonism 1.2. Role of Protein Tyrosine Kinases and Protein Tyrosine Phosphatases Antagonism Impaired insulin signaling is a common feature of the pathophysiology of human Impairedobesity insulin and signaling T2DM. is Although, a common several feature studies of the have pathophysiology increased the knowledge of human regarding the obesity and T2DM.role of Although, reversible tyrosineseveral phosphorylationstudies have increased of the insulin the knowledge receptor and regarding its substrate proteins the role of reversiblein the mechanism tyrosine phosphorylat of insulin actionion (Figureof the insulin1), it is stillreceptor necessary and toits furthersubstrate investigate how Int. J. Mol.