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Jesse Rinehart, PhD

Associate Professor

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Jesse Rinehart, PhD

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Rinehart Lab
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Research Summary

Our laboratory is focused on the discovery and characterization of novel sites of phosphorylation in kinases and regulatory networks of proteins that control electrolyte homeostasis. Our long term goal is to understand and “decode” complex signaling networks in physiological systems. Our research integrates cutting edge proteomics with mainstay techniques of molecular biology and physiology, to study signaling networks and provide critical new insight into regulated ion transport. We are focusing on mechanisms of cellular signaling transduction that involve protein phosphorylation. Many of the cellular signaling mechanisms that are disrupted in disease states, and are assumed to be fundamental for normal cellular physiology, are largely uncharacterized and hold a vast amount of therapeutic potential. Understanding the human phosphoproteome is a major challenge as research continues ever farther into the post genome era. We therefore employ established quantitative proteomic techniques, and aim to develop novel methods, in an effort to decode new signaling pathways. We aim to find new roles for kinases, phosphatases, their substrates, and protein-protein interactions on a system-wide level. Collectively, we hope these efforts will identify molecular mechanisms important for both healthy and disease states in humans.

Tens of thousands of phosphorylation sites in diverse eukaryotic proteins have been identified through large scale mass spectrometry studies. For the great majority of these sites, however, the responsible kinase is unknown, and the functional role of phosphorylation is not understood. We have recently made substantial progress towards narrowing this critical gap in knowledge with a new technology that enables site-specific incorporation of phosphoserine into proteins. This technology utilizes an E. coli strain with an expanded genetic code and contains a dedicated sense codon for phosphoserine. We use this breakthrough technology to synthesize human phosphoproteins and accelerate our efforts in “decoding” the human phosphoproteome.

Specialized Terms: Physiological Systems; Protein Phosphorylation; Cell Signaling; Phosphoproteomics; Protein Engineering; Ion Transport; Synthetic Biology; Translational Research

Learn more at http://rinehart.commons.yale.edu/

Coauthors

Research Interests

Biochemistry; Biotechnology; Hypertension; Molecular Biology; Phosphoproteins; Signal Transduction; Proteomics; Systems Biology; Synthetic Biology

Research Images

How phosphoryation controls cell volume
Featured on the cover of Cell. K-Cl cotransporters (KCCs) control transmembrane electrolyte flux in a variety of physiologic settings, including the acute response to altered extracellular osmolarity. We used targeted phosphoproteomics to reveal how phosphorylation at two conserved sites in KCCs controls their activity.

Selected Publications

  • Phosphorylated WNK kinase networks in recoded bacteria recapitulate physiological functionSchiapparelli P, Pirman NL, Mohler K, Miranda-Herrera PA, Zarco N, Kilic O, Miller C, Shah SR, Rogulina S, Hungerford W, Abriola L, Hoyer D, Turk BE, Guerrero-Cázares H, Isaacs FJ, Quiñones-Hinojosa A, Levchenko A, Rinehart J. Phosphorylated WNK kinase networks in recoded bacteria recapitulate physiological function Cell Reports 2021, 36: 109416. PMID: 34289367, PMCID: PMC8379681, DOI: 10.1016/j.celrep.2021.109416.
  • Targeting Pyruvate Kinase M2 Phosphorylation Reverses Aggressive Cancer PhenotypesApostolidi M, Vathiotis IA, Muthusamy V, Gaule P, Gassaway BM, Rimm DL, Rinehart J. Targeting Pyruvate Kinase M2 Phosphorylation Reverses Aggressive Cancer Phenotypes Cancer Research 2021, 81: 4346-4359. PMID: 34185676, PMCID: PMC8373815, DOI: 10.1158/0008-5472.can-20-4190.
  • A flexible codon in genomically recoded Escherichia coli permits programmable protein phosphorylationPirman NL, Barber KW, Aerni HR, Ma NJ, Haimovich AD, Rogulina S, Isaacs FJ, Rinehart J. A flexible codon in genomically recoded Escherichia coli permits programmable protein phosphorylation Nature Communications 2015, 6: 8130. PMID: 26350500, PMCID: PMC4566969, DOI: 10.1038/ncomms9130.
  • Genomically Recoded Organisms Expand Biological FunctionsLajoie MJ, Rovner AJ, Goodman DB, Aerni HR, Haimovich AD, Kuznetsov G, Mercer JA, Wang HH, Carr PA, Mosberg JA, Rohland N, Schultz PG, Jacobson JM, Rinehart J, Church GM, Isaacs FJ. Genomically Recoded Organisms Expand Biological Functions Science 2013, 342: 357-360. PMID: 24136966, PMCID: PMC4924538, DOI: 10.1126/science.1241459.
  • Encoding human serine phosphopeptides in bacteria for proteome-wide identification of phosphorylation-dependent interactionsBarber KW, Muir P, Szeligowski RV, Rogulina S, Gerstein M, Sampson JR, Isaacs FJ, Rinehart J. Encoding human serine phosphopeptides in bacteria for proteome-wide identification of phosphorylation-dependent interactions Nature Biotechnology 2018, 36: 638-644. PMID: 29889213, PMCID: PMC6590076, DOI: 10.1038/nbt.4150.
  • Enhanced access to the human phosphoproteome with genetically encoded phosphothreonineMoen J, Mohler K, Rogulina S, Shi X, Shen H, Rinehart J. Enhanced access to the human phosphoproteome with genetically encoded phosphothreonine Nature Communications 2022, 13: 7226. PMID: 36433969, PMCID: PMC9700786, DOI: 10.1038/s41467-022-34980-5.
  • Correction: The mechanism of β-N-methylamino-L-alanine inhibition of tRNA aminoacylation and its impact on misincorporationHan N, Bullwinkle T, Loeb K, Faull K, Mohler K, Rinehart J, Ibba M. Correction: The mechanism of β-N-methylamino-L-alanine inhibition of tRNA aminoacylation and its impact on misincorporation Journal Of Biological Chemistry 2022, 298: 102544. PMCID: PMC9547288, DOI: 10.1016/j.jbc.2022.102544.
  • CSIG-08. TARGETING ION TRANSPORT-REGULATORY KINASES AS A NOVEL TREATMENT FOR GLIOBLASTOMASchiapparelli P, Meade P, Miranda-Herrera P, Bechtle A, Issacs F, Levchenko A, Rinehart J, Quinones-Hinojosa A. CSIG-08. TARGETING ION TRANSPORT-REGULATORY KINASES AS A NOVEL TREATMENT FOR GLIOBLASTOMA Neuro-Oncology 2020, 22: ii29-ii29. PMCID: PMC7650317, DOI: 10.1093/neuonc/noaa215.120.
  • 205-OR: Hepatic Protein Kinase C-e Is Necessary and Sufficient in Mediating Lipid-Induced Hepatic Insulin ResistanceLYU K, ZHANG D, KAHN M, RODRIGUES M, HIRABARA S, LUUKKONEN P, LEE S, BHANOT S, RINEHART J, BLUME N, RASCH M, SERLIE M, BOGAN J, CLINE G, SAMUEL V, SHULMAN G. 205-OR: Hepatic Protein Kinase C-e Is Necessary and Sufficient in Mediating Lipid-Induced Hepatic Insulin Resistance Diabetes 2020, 69 DOI: 10.2337/db20-205-or.
  • The mechanism of β-N-methylamino-l-alanine inhibition of tRNA aminoacylation and its impact on misincorporationHan N, Bullwinkle T, Loeb K, Faull K, Mohler K, Rinehart J, Ibba M. The mechanism of β-N-methylamino-l-alanine inhibition of tRNA aminoacylation and its impact on misincorporation Journal Of Biological Chemistry 2020, 295: 1402-1410. DOI: 10.1016/s0021-9258(17)49898-x.
  • Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose ProductionGassaway BM, Cardone RL, Padyana AK, Petersen MC, Judd ET, Hayes S, Tong S, Barber KW, Apostolidi M, Abulizi A, Sheetz JB, Kshitiz, Aerni HR, Gross S, Kung C, Samuel VT, Shulman GI, Kibbey RG, Rinehart J. Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production Cell Reports 2019, 29: 3394-3404.e9. PMID: 31825824, PMCID: PMC6951436, DOI: 10.1016/j.celrep.2019.11.009.
  • Evolution of translation machinery in recoded bacteria enables multi-site incorporation of nonstandard amino acidsAmiram M, Haimovich AD, Fan C, Wang YS, Aerni HR, Ntai I, Moonan DW, Ma NJ, Rovner AJ, Hong SH, Kelleher NL, Goodman AL, Jewett MC, Söll D, Rinehart J, Isaacs FJ. Evolution of translation machinery in recoded bacteria enables multi-site incorporation of nonstandard amino acids Nature Biotechnology 2015, 33: 1272-1279. PMID: 26571098, PMCID: PMC4784704, DOI: 10.1038/nbt.3372.
  • The PINK1-PARKIN Mitochondrial Ubiquitylation Pathway Drives a Program of OPTN/NDP52 Recruitment and TBK1 Activation to Promote MitophagyHeo JM, Ordureau A, Paulo JA, Rinehart J, Harper JW. The PINK1-PARKIN Mitochondrial Ubiquitylation Pathway Drives a Program of OPTN/NDP52 Recruitment and TBK1 Activation to Promote Mitophagy Molecular Cell 2015, 60: 7-20. PMID: 26365381, PMCID: PMC4592482, DOI: 10.1016/j.molcel.2015.08.016.
  • Robust production of recombinant phosphoproteins using cell-free protein synthesisOza JP, Aerni HR, Pirman NL, Barber KW, ter Haar CM, Rogulina S, Amrofell MB, Isaacs FJ, Rinehart J, Jewett MC. Robust production of recombinant phosphoproteins using cell-free protein synthesis Nature Communications 2015, 6: 8168. PMID: 26350765, PMCID: PMC4566161, DOI: 10.1038/ncomms9168.
  • Innentitelbild: Chemische Evolution eines bakteriellen Proteoms (Angew. Chem. 34/2015)Hoesl M, Oehm S, Durkin P, Darmon E, Peil L, Aerni H, Rappsilber J, Rinehart J, Leach D, Söll D, Budisa N. Innentitelbild: Chemische Evolution eines bakteriellen Proteoms (Angew. Chem. 34/2015) Angewandte Chemie 2015, 127: 9862-9862. DOI: 10.1002/ange.201506522.
  • Inside Cover: Chemical Evolution of a Bacterial Proteome (Angew. Chem. Int. Ed. 34/2015)Hoesl M, Oehm S, Durkin P, Darmon E, Peil L, Aerni H, Rappsilber J, Rinehart J, Leach D, Söll D, Budisa N. Inside Cover: Chemical Evolution of a Bacterial Proteome (Angew. Chem. Int. Ed. 34/2015) Angewandte Chemie International Edition 2015, 54: 9726-9726. DOI: 10.1002/anie.201506522.
  • Chemische Evolution eines bakteriellen ProteomsHoesl M, Oehm S, Durkin P, Darmon E, Peil L, Aerni H, Rappsilber J, Rinehart J, Leach D, Söll D, Budisa N. Chemische Evolution eines bakteriellen Proteoms Angewandte Chemie 2015, 127: 10168-10172. DOI: 10.1002/ange.201502868.
  • Mineralocorticoid Receptor Phosphorylation Regulates Ligand Binding and Renal Response to Volume Depletion and HyperkalemiaShibata S, Rinehart J, Zhang J, Moeckel G, Castañeda-Bueno M, Stiegler AL, Boggon TJ, Gamba G, Lifton RP. Mineralocorticoid Receptor Phosphorylation Regulates Ligand Binding and Renal Response to Volume Depletion and Hyperkalemia Cell Metabolism 2013, 18: 660-671. PMID: 24206662, PMCID: PMC3909709, DOI: 10.1016/j.cmet.2013.10.005.
  • Src‐family tyrosine kinase (SFK) phosphorylates With‐No‐ Lysine Kinase4 (WNK4) and modulates the inhibitory effect of WNK4 on ROMK channels.Lin D, Yue P, Yarborough O, Lifton R, Rinehart J, Wang W. Src‐family tyrosine kinase (SFK) phosphorylates With‐No‐ Lysine Kinase4 (WNK4) and modulates the inhibitory effect of WNK4 on ROMK channels. The FASEB Journal 2013, 27: 911.2-911.2. DOI: 10.1096/fasebj.27.1_supplement.911.2.
  • Src‐family protein tyrosine kinase (SFK) stimulates KCNJ10 K channels in the basolateral membrane of distal convoluted tubules (DCT).Wang W, Zhang C, Lin D, Yue P, Wang L, Rinehart J. Src‐family protein tyrosine kinase (SFK) stimulates KCNJ10 K channels in the basolateral membrane of distal convoluted tubules (DCT). The FASEB Journal 2013, 27: 911.1-911.1. DOI: 10.1096/fasebj.27.1_supplement.911.1.
  • Expanding the Genetic Code of Escherichia coli with PhosphoserinePark HS, Hohn MJ, Umehara T, Guo LT, Osborne EM, Benner J, Noren CJ, Rinehart J, Söll D. Expanding the Genetic Code of Escherichia coli with Phosphoserine Science 2011, 333: 1151-1154. PMID: 21868676, PMCID: PMC5547737, DOI: 10.1126/science.1207203.
  • Sec23b deficiency In Mice Results In Pancreatic Destruction and Defective long Term Hematopoietic Stem Cell FunctionVasievich M, Zhang B, Rinehart J, Jones M, Maillard I, Ginsburg D. Sec23b deficiency In Mice Results In Pancreatic Destruction and Defective long Term Hematopoietic Stem Cell Function Blood 2010, 116: 2038-2038. DOI: 10.1182/blood.v116.21.2038.2038.
  • Sites of Regulated Phosphorylation that Control K-Cl Cotransporter ActivityRinehart J, Maksimova Y, Tanis J, Stone K, Hodson C, Zhang J, Risinger M, Pan W, Wu D, Colangelo C. Sites of Regulated Phosphorylation that Control K-Cl Cotransporter Activity Journal Of End-to-End-testing 2009, 138: 525-536. DOI: 10.1016/s9999-9994(09)20390-4.
  • Sites of Regulated Phosphorylation that Control K-Cl Cotransporter ActivityRinehart J, Maksimova Y, Tanis J, Stone K, Hodson C, Zhang J, Risinger M, Pan W, Wu D, Colangelo C, Forbush B, Joiner C, Gulcicek E, Gallagher P, Lifton R. Sites of Regulated Phosphorylation that Control K-Cl Cotransporter Activity Journal Of End-to-End-testing 2009, 138: 525-536. DOI: 10.1016/s9999-9994(09)20441-7.
  • Sites of Regulated Phosphorylation that Control K-Cl Cotransporter ActivityRinehart J, Maksimova YD, Tanis JE, Stone KL, Hodson CA, Zhang J, Risinger M, Pan W, Wu D, Colangelo CM, Forbush B, Joiner CH, Gulcicek EE, Gallagher PG, Lifton RP. Sites of Regulated Phosphorylation that Control K-Cl Cotransporter Activity Cell 2009, 138: 525-536. PMID: 19665974, PMCID: PMC2811214, DOI: 10.1016/j.cell.2009.05.031.
  • Structural and Functional Interactions of KCl Cotransport Proteins KCC1 and KCC3 in Sickle and Normal Erythrocyte MembranesRisinger M, Risinger M, Rinehart J, Crable S, Crable S, Ottlinger A, Ottlinger A, Winkelmann R, Winkelmann R, Pan D, Pan D, Huebner C, Huebner C, Gallagher P, Joiner C, Joiner C. Structural and Functional Interactions of KCl Cotransport Proteins KCC1 and KCC3 in Sickle and Normal Erythrocyte Membranes Blood 2008, 112: 2474-2474. DOI: 10.1182/blood.v112.11.2474.2474.
  • A mutation in WNK4 that causes human hypertension activates the epithelial Na+ channel in vivoRing A, Kahle K, Cheng S, Leng Q, Lalioti M, Wilson F, Rinehart J, Hebert S, Lifton R. A mutation in WNK4 that causes human hypertension activates the epithelial Na+ channel in vivo The FASEB Journal 2007, 21: a876-a876. DOI: 10.1096/fasebj.21.6.a876-c.
  • Catalytically‐inactive WNK3 bypasses the tonicity requirement for K‐Cl cotransporter activation via a phosphatase‐dependent pathwayDe los Heros P, Kahle K, Rinehart J, Bobadilla N, San Cristobal P, Vazquez N, Lifton R, Hebert S, Gamba G. Catalytically‐inactive WNK3 bypasses the tonicity requirement for K‐Cl cotransporter activation via a phosphatase‐dependent pathway The FASEB Journal 2006, 20: a1224-a1224. DOI: 10.1096/fasebj.20.5.a1224.
  • Saccharomyces cerevisiae imports the cytosolic pathway for Gln‐tRNA synthesis into the mitochondrionKrett B, Rinehart J, Rubio M, Alfonzo J, Söll D. Saccharomyces cerevisiae imports the cytosolic pathway for Gln‐tRNA synthesis into the mitochondrion The FASEB Journal 2006, 20: a500-a500. DOI: 10.1096/fasebj.20.4.a500-b.
  • Genomics and the evolution of aminoacyl-tRNA synthesis.Ruan B, Ahel I, Ambrogelly A, Becker H, Bunjun S, Feng L, Tumbula-Hansen D, Ibba M, Korencic D, Kobayashi H, Jacquin-Becker C, Mejlhede N, Min B, Raczniak G, Rinehart J, Stathopoulos C, Li T, Söll D. Genomics and the evolution of aminoacyl-tRNA synthesis. Acta Biochimica Polonica 2001, 48: 313-21. PMID: 11732603, DOI: 10.18388/abp.2001_3917.
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