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Michael Caplan, PhD, MD

C. N. H. Long Professor of Cellular And Molecular Physiology and Professor of Cell Biology; Chair, Cellular and Molecular Physiology

Contact Information

Michael Caplan, PhD, MD

Mailing Address

  • Cellular & Molecular Physiology

    PO Box 208026, 333 Cedar Street

    New Haven, CT 06520-8026

    United States

Research Summary

The surface membranes of epithelial cells are divided into domains characterized by dramatically different protein compositions. Membrane proteins whose distributions are restricted to one of these domains must incorporate information that specifies their appropriate destinations. We seek to determine how this information is encoded and how it is interpreted.

Our studies of cellular trafficking focus on proteins involved in ion transport, as well as on the proteins associated with polycystic kidney disease. Polycystic kidney disease is a prevalent and serious genetic disorder that distorts the normal architecture of renal epithelial cells and that is a major cause of kidney failure. The Caplan laboratory is working to understand the mechanisms responsible for this condition and to identify targets for new therapies


Specialized Terms: Ion pumps in polarized epithelia; Sorting and function; Polycystic kidney disease

Extensive Research Description

Work in the Caplan laboratory is focused on understanding how membrane proteins are sorted to the appropriate cell surface domains of polarized epithelial cells. One of the proteins whose trafficking we study is the Na,K-ATPase, or sodium pump, which generates the ion gradients responsible for most fluid and electrolyte transport processes in the kidney. The Na,K-ATPase must be restricted to the basolateral surfaces of renal tubule epithelial cells. Much remains to be learned about the partner proteins and trafficking pathways that determine the sodium pump’s subcellular distribution and modulate its activity. We have adapted a novel labeling methodology to investigate the attributes of temporally defined cohorts of Na,K-ATPase.

We can observe directly the trafficking itinerary pursued by newly synthesized Na,K-ATPase and isolate newly synthesized Na,K-ATPase in association with its collections of partner proteins. We find that the basolateral delivery of newly synthesized Na,K-ATPase occurs via a pathway distinct from that pursued by other basolateral membrane proteins. We have also detected interactions between the Na,K-ATPase a-subunit and a collection of novel partner proteins that may govern the pump’s trafficking properties. Thus, we have developed tools that permit us to evaluate the trafficking pathways and partner proteins that govern the post-synthetic sorting and regulation of the epithelial Na,K-ATPase.

We also study a common genetic disease that dramatically alters the structure and function of polarized epithelial cells. In Autosomal Dominant Polycystic Kidney Disease (ADPKD) the normal architecture of the kidney tubules is replaced by large fluid filled cysts, which can ultimately result in renal failure. ADPKD is caused by mutations in the PKD1 or PKD2 genes, which encode the polycystin-1 and polycystin-2 proteins, respectively. Both of these proteins are targeted to cilia in polarized epithelial cells. We have found that polycystin-1 undergoes such a proteolytic cleavage that releases its C-terminal tail (CTT), which enters the nucleus and initiates signaling processes. The cleavage occurs in vivo in association with alterations in mechanical stimuli that may be communicated by signaling through the cilium. The C-terminal tail fragment of polycystin-1 participates in a complex with ß-catenin and acts to profoundly inhibit canonical ß-catenin-dependent Wnt signaling. The polycystin-1 C-terminal tail fragment also appears to modulate gene expression, and may induce expression of cilia-related proteins in renal epithelial cells.

We find that all of the signal transduction machinery found in the cilia of olfactory epithelial cells is present in renal epithelial cells. Our data suggest that olfactory receptors and proteins involved in olfactory signal transduction may play a role in regulating renal flow or transport in response to chemosensory cues.

Coauthors

Research Interests

Cell Biology; Epithelial Cells; Kidney; Polycystic Kidney Diseases; Physiology; Ion Pumps

Selected Publications

  • Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus.Chauvet V, Tian X, Husson H, Grimm DH, Wang T, Hiesberger T, Igarashi P, Bennett AM, Ibraghimov-Beskrovnaya O, Somlo S, Caplan MJ. Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus. The Journal Of Clinical Investigation 2004, 114: 1433-43. PMID: 15545994, PMCID: PMC525739, DOI: 10.1172/JCI21753.
  • The C-terminal tail of the polycystin-1 protein interacts with the Na,K-ATPase alpha-subunit.Zatti A, Chauvet V, Rajendran V, Kimura T, Pagel P, Caplan MJ. The C-terminal tail of the polycystin-1 protein interacts with the Na,K-ATPase alpha-subunit. Molecular Biology Of The Cell 2005, 16: 5087-93. PMID: 16107561, PMCID: PMC1266409, DOI: 10.1091/mbc.e05-03-0200.
  • AMP-activated protein kinase regulates the assembly of epithelial tight junctions.Zhang L, Li J, Young LH, Caplan MJ. AMP-activated protein kinase regulates the assembly of epithelial tight junctions. Proceedings Of The National Academy Of Sciences Of The United States Of America 2006, 103: 17272-7. PMID: 17088526, PMCID: PMC1859922, DOI: 10.1073/pnas.0608531103.
  • Polycystin-2 regulates proliferation and branching morphogenesis in kidney epithelial cells.Grimm DH, Karihaloo A, Cai Y, Somlo S, Cantley LG, Caplan MJ. Polycystin-2 regulates proliferation and branching morphogenesis in kidney epithelial cells. The Journal Of Biological Chemistry 2006, 281: 137-44. PMID: 16278216, DOI: 10.1074/jbc.M507845200.
  • Arrestins and spinophilin competitively regulate Na+,K+-ATPase trafficking through association with a large cytoplasmic loop of the Na+,K+-ATPase.Kimura T, Allen PB, Nairn AC, Caplan MJ. Arrestins and spinophilin competitively regulate Na+,K+-ATPase trafficking through association with a large cytoplasmic loop of the Na+,K+-ATPase. Molecular Biology Of The Cell 2007, 18: 4508-18. PMID: 17804821, PMCID: PMC2043564, DOI: 10.1091/mbc.E06-08-0711.
  • Tetraspan proteins: regulators of renal structure and function.Caplan MJ, Kamsteeg EJ, Duffield A. Tetraspan proteins: regulators of renal structure and function. Current Opinion In Nephrology And Hypertension 2007, 16: 353-8. PMID: 17565278, DOI: 10.1097/MNH.0b013e328177b1fa.
  • MAL decreases the internalization of the aquaporin-2 water channel.Kamsteeg EJ, Duffield AS, Konings IB, Spencer J, Pagel P, Deen PM, Caplan MJ. MAL decreases the internalization of the aquaporin-2 water channel. Proceedings Of The National Academy Of Sciences Of The United States Of America 2007, 104: 16696-701. PMID: 17940053, PMCID: PMC2034241, DOI: 10.1073/pnas.0708023104.
  • Polycystin-1 C-terminal tail associates with beta-catenin and inhibits canonical Wnt signaling.Lal M, Song X, Pluznick JL, Di Giovanni V, Merrick DM, Rosenblum ND, Chauvet V, Gottardi CJ, Pei Y, Caplan MJ. Polycystin-1 C-terminal tail associates with beta-catenin and inhibits canonical Wnt signaling. Human Molecular Genetics 2008, 17: 3105-17. PMID: 18632682, PMCID: PMC2722884, DOI: 10.1093/hmg/ddn208.
  • Exon loss accounts for differential sorting of Na-K-Cl cotransporters in polarized epithelial cells.Carmosino M, Giménez I, Caplan M, Forbush B. Exon loss accounts for differential sorting of Na-K-Cl cotransporters in polarized epithelial cells. Molecular Biology Of The Cell 2008, 19: 4341-51. PMID: 18667527, PMCID: PMC2555935, DOI: 10.1091/mbc.E08-05-0478.
  • Expression of tetraspan protein CD63 activates protein-tyrosine kinase (PTK) and enhances the PTK-induced inhibition of ROMK channels.Lin D, Kamsteeg EJ, Zhang Y, Jin Y, Sterling H, Yue P, Roos M, Duffield A, Spencer J, Caplan M, Wang WH. Expression of tetraspan protein CD63 activates protein-tyrosine kinase (PTK) and enhances the PTK-induced inhibition of ROMK channels. The Journal Of Biological Chemistry 2008, 283: 7674-81. PMID: 18211905, DOI: 10.1074/jbc.M705574200.
  • Functional expression of the olfactory signaling system in the kidney.Pluznick JL, Zou DJ, Zhang X, Yan Q, Rodriguez-Gil DJ, Eisner C, Wells E, Greer CA, Wang T, Firestein S, Schnermann J, Caplan MJ. Functional expression of the olfactory signaling system in the kidney. Proceedings Of The National Academy Of Sciences Of The United States Of America 2009, 106: 2059-64. PMID: 19174512, PMCID: PMC2644163, DOI: 10.1073/pnas.0812859106.
  • Membrane proteins follow multiple pathways to the basolateral cell surface in polarized epithelial cells.Farr GA, Hull M, Mellman I, Caplan MJ. Membrane proteins follow multiple pathways to the basolateral cell surface in polarized epithelial cells. The Journal Of Cell Biology 2009, 186: 269-82. PMID: 19620635, PMCID: PMC2717640, DOI: 10.1083/jcb.200901021.
  • Polycystin-1 C-terminal cleavage is modulated by polycystin-2 expression.Bertuccio CA, Chapin HC, Cai Y, Mistry K, Chauvet V, Somlo S, Caplan MJ. Polycystin-1 C-terminal cleavage is modulated by polycystin-2 expression. The Journal Of Biological Chemistry 2009, 284: 21011-26. PMID: 19491093, PMCID: PMC2742866, DOI: 10.1074/jbc.M109.017756.
  • The cell biology of polycystic kidney disease.Chapin HC, Caplan MJ. The cell biology of polycystic kidney disease. The Journal Of Cell Biology 2010, 191: 701-10. PMID: 21079243, PMCID: PMC2983067, DOI: 10.1083/jcb.201006173.
  • Association with {beta}-COP regulates the trafficking of the newly synthesized Na,K-ATPase.Morton MJ, Farr GA, Hull M, Capendeguy O, Horisberger JD, Caplan MJ. Association with {beta}-COP regulates the trafficking of the newly synthesized Na,K-ATPase. The Journal Of Biological Chemistry 2010, 285: 33737-46. PMID: 20801885, PMCID: PMC2962472, DOI: 10.1074/jbc.M110.141119.
  • Polycystin-1 surface localization is stimulated by polycystin-2 and cleavage at the G protein-coupled receptor proteolytic site.Chapin HC, Rajendran V, Caplan MJ. Polycystin-1 surface localization is stimulated by polycystin-2 and cleavage at the G protein-coupled receptor proteolytic site. Molecular Biology Of The Cell 2010, 21: 4338-48. PMID: 20980620, PMCID: PMC3002387, DOI: 10.1091/mbc.E10-05-0407.
  • AS160 associates with the Na+,K+-ATPase and mediates the adenosine monophosphate-stimulated protein kinase-dependent regulation of sodium pump surface expression.Alves DS, Farr GA, Seo-Mayer P, Caplan MJ. AS160 associates with the Na+,K+-ATPase and mediates the adenosine monophosphate-stimulated protein kinase-dependent regulation of sodium pump surface expression. Molecular Biology Of The Cell 2010, 21: 4400-8. PMID: 20943949, PMCID: PMC3002392, DOI: 10.1091/mbc.E10-06-0507.
  • Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling.Chairoungdua A, Smith DL, Pochard P, Hull M, Caplan MJ. Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling. The Journal Of Cell Biology 2010, 190: 1079-91. PMID: 20837771, PMCID: PMC3101591, DOI: 10.1083/jcb.201002049.
  • MAL/VIP17, a new player in the regulation of NKCC2 in the kidney.Carmosino M, Rizzo F, Procino G, Basco D, Valenti G, Forbush B, Schaeren-Wiemers N, Caplan MJ, Svelto M. MAL/VIP17, a new player in the regulation of NKCC2 in the kidney. Molecular Biology Of The Cell 2010, 21: 3985-97. PMID: 20861303, PMCID: PMC2982131, DOI: 10.1091/mbc.E10-05-0456.
  • AMP-activated protein kinase (AMPK) activation and glycogen synthase kinase-3β (GSK-3β) inhibition induce Ca2+-independent deposition of tight junction components at the plasma membrane.Zhang L, Jouret F, Rinehart J, Sfakianos J, Mellman I, Lifton RP, Young LH, Caplan MJ. AMP-activated protein kinase (AMPK) activation and glycogen synthase kinase-3β (GSK-3β) inhibition induce Ca2+-independent deposition of tight junction components at the plasma membrane. The Journal Of Biological Chemistry 2011, 286: 16879-90. PMID: 21383016, PMCID: PMC3089531, DOI: 10.1074/jbc.M110.186932.
  • Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis.Takiar V, Nishio S, Seo-Mayer P, King JD, Li H, Zhang L, Karihaloo A, Hallows KR, Somlo S, Caplan MJ. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 2462-7. PMID: 21262823, PMCID: PMC3038735, DOI: 10.1073/pnas.1011498108.
  • Preactivation of AMPK by metformin may ameliorate the epithelial cell damage caused by renal ischemia.Seo-Mayer PW, Thulin G, Zhang L, Alves DS, Ardito T, Kashgarian M, Caplan MJ. Preactivation of AMPK by metformin may ameliorate the epithelial cell damage caused by renal ischemia. American Journal Of Physiology. Renal Physiology 2011, 301: F1346-57. PMID: 21849490, PMCID: PMC3233870, DOI: 10.1152/ajprenal.00420.2010.
  • Regulated intramembrane proteolysis: signaling pathways and biological functions.Lal M, Caplan M. Regulated intramembrane proteolysis: signaling pathways and biological functions. Physiology (Bethesda, Md.) 2011, 26: 34-44. PMID: 21357901, DOI: 10.1152/physiol.00028.2010.
  • Polycystic kidney disease: pathogenesis and potential therapies.Takiar V, Caplan MJ. Polycystic kidney disease: pathogenesis and potential therapies. Biochimica Et Biophysica Acta 2011, 1812: 1337-43. PMID: 21146605, PMCID: PMC3139769, DOI: 10.1016/j.bbadis.2010.11.014.
  • The γ-secretase cleavage product of polycystin-1 regulates TCF and CHOP-mediated transcriptional activation through a p300-dependent mechanism.Merrick D, Chapin H, Baggs JE, Yu Z, Somlo S, Sun Z, Hogenesch JB, Caplan MJ. The γ-secretase cleavage product of polycystin-1 regulates TCF and CHOP-mediated transcriptional activation through a p300-dependent mechanism. Developmental Cell 2012, 22: 197-210. PMID: 22178500, PMCID: PMC3264829, DOI: 10.1016/j.devcel.2011.10.028.
  • Activation of the Ca²+-sensing receptor induces deposition of tight junction components to the epithelial cell plasma membrane.Jouret F, Wu J, Hull M, Rajendran V, Mayr B, Schöfl C, Geibel J, Caplan MJ. Activation of the Ca²+-sensing receptor induces deposition of tight junction components to the epithelial cell plasma membrane. Journal Of Cell Science 2013, 126: 5132-42. PMID: 24013548, PMCID: PMC3828589, DOI: 10.1242/jcs.127555.
  • Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation.Pluznick JL, Protzko RJ, Gevorgyan H, Peterlin Z, Sipos A, Han J, Brunet I, Wan LX, Rey F, Wang T, Firestein SJ, Yanagisawa M, Gordon JI, Eichmann A, Peti-Peterdi J, Caplan MJ. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 4410-5. PMID: 23401498, PMCID: PMC3600440, DOI: 10.1073/pnas.1215927110.
  • Trafficking to the apical and basolateral membranes in polarized epithelial cells.Stoops EH, Caplan MJ. Trafficking to the apical and basolateral membranes in polarized epithelial cells. Journal Of The American Society Of Nephrology : JASN 2014, 25: 1375-86. PMID: 24652803, PMCID: PMC4073435, DOI: 10.1681/ASN.2013080883.
  • The periciliary ring in polarized epithelial cells is a hot spot for delivery of the apical protein gp135.Stoops EH, Hull M, Olesen C, Mistry K, Harder JL, Rivera-Molina F, Toomre D, Caplan MJ. The periciliary ring in polarized epithelial cells is a hot spot for delivery of the apical protein gp135. The Journal Of Cell Biology 2015, 211: 287-94. PMID: 26504168, PMCID: PMC4621837, DOI: 10.1083/jcb.201502045.
  • Akt Substrate of 160 kD Regulates Na+,K+-ATPase Trafficking in Response to Energy Depletion and Renal Ischemia.Alves DS, Thulin G, Loffing J, Kashgarian M, Caplan MJ. Akt Substrate of 160 kD Regulates Na+,K+-ATPase Trafficking in Response to Energy Depletion and Renal Ischemia. Journal Of The American Society Of Nephrology : JASN 2015, 26: 2765-76. PMID: 25788531, PMCID: PMC4625659, DOI: 10.1681/ASN.2013101040.
  • Dual pulse-chase microscopy reveals early divergence in the biosynthetic trafficking of the Na,K-ATPase and E-cadherin.Farr GA, Hull M, Stoops EH, Bateson R, Caplan MJ. Dual pulse-chase microscopy reveals early divergence in the biosynthetic trafficking of the Na,K-ATPase and E-cadherin. Molecular Biology Of The Cell 2015, 26: 4401-11. PMID: 26424804, PMCID: PMC4666135, DOI: 10.1091/mbc.E14-09-1385.
  • Newly synthesized and recycling pools of the apical protein gp135 do not occupy the same compartments.Stoops EH, Hull M, Caplan MJ. Newly synthesized and recycling pools of the apical protein gp135 do not occupy the same compartments. Traffic (Copenhagen, Denmark) 2016, 17: 1272-1285. PMID: 27649479, PMCID: PMC5123909, DOI: 10.1111/tra.12449.
  • The secretory pathway at 50: a golden anniversary for some momentous grains of silver.Matlin KS, Caplan MJ. The secretory pathway at 50: a golden anniversary for some momentous grains of silver. Molecular Biology Of The Cell 2017, 28: 229-232. PMID: 28082520, PMCID: PMC5231891, DOI: 10.1091/mbc.E16-07-0508.
  • The polycystins are modulated by cellular oxygen-sensing pathways and regulate mitochondrial function.Padovano V, Kuo IY, Stavola LK, Aerni HR, Flaherty BJ, Chapin HC, Ma M, Somlo S, Boletta A, Ehrlich BE, Rinehart J, Caplan MJ. The polycystins are modulated by cellular oxygen-sensing pathways and regulate mitochondrial function. Molecular Biology Of The Cell 2017, 28: 261-269. PMID: 27881662, PMCID: PMC5231895, DOI: 10.1091/mbc.E16-08-0597.
  • Metabolism and mitochondria in polycystic kidney disease research and therapy.Padovano V, Podrini C, Boletta A, Caplan MJ. Metabolism and mitochondria in polycystic kidney disease research and therapy. Nature Reviews. Nephrology 2018, 14: 678-687. PMID: 30120380, DOI: 10.1038/s41581-018-0051-1.
  • Newly synthesized polycystin-1 takes different trafficking pathways to the apical and ciliary membranes.Gilder AL, Chapin HC, Padovano V, Hueschen CL, Rajendran V, Caplan MJ. Newly synthesized polycystin-1 takes different trafficking pathways to the apical and ciliary membranes. Traffic (Copenhagen, Denmark) 2018, 19: 933-945. PMID: 30125442, PMCID: PMC6237641, DOI: 10.1111/tra.12612.
  • The Polycystin Complex Reveals Its Complexity.Padovano V, Caplan MJ. The Polycystin Complex Reveals Its Complexity. Biochemistry 2018, 57: 6917-6918. PMID: 30540438, DOI: 10.1021/acs.biochem.8b01205.
  • Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ.Merrick D, Mistry K, Wu J, Gresko N, Baggs JE, Hogenesch JB, Sun Z, Caplan MJ. Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ. Human Molecular Genetics 2019, 28: 16-30. PMID: 30215740, PMCID: PMC6298236, DOI: 10.1093/hmg/ddy322.
  • Holding open the door reveals a new view of polycystin channel function.Caplan MJ. Holding open the door reveals a new view of polycystin channel function. EMBO Reports 2019, 20: e49156. PMID: 31556469, PMCID: PMC6832007, DOI: 10.15252/embr.201949156.
  • Mechanisms involved in AMPK-mediated deposition of tight junction components to the plasma membrane.Wu J, Rowart P, Jouret F, Gassaway BM, Rajendran V, Rinehart J, Caplan MJ. Mechanisms involved in AMPK-mediated deposition of tight junction components to the plasma membrane. American Journal Of Physiology. Cell Physiology 2020, 318: C486-C501. PMID: 31913699, PMCID: PMC7099514, DOI: 10.1152/ajpcell.00422.2019.
  • A cut above (and below): Protein cleavage in the regulation of polycystin trafficking and signaling.Padovano V, Mistry K, Merrick D, Gresko N, Caplan MJ. A cut above (and below): Protein cleavage in the regulation of polycystin trafficking and signaling. Cellular Signalling 2020, 72: 109634. PMID: 32283256, PMCID: PMC7269866, DOI: 10.1016/j.cellsig.2020.109634.
  • Chloride channels regulate differentiation and barrier functions of the mammalian airway.He M, Wu B, Ye W, Le DD, Sinclair AW, Padovano V, Chen Y, Li KX, Sit R, Tan M, Caplan MJ, Neff N, Jan YN, Darmanis S, Jan LY. Chloride channels regulate differentiation and barrier functions of the mammalian airway. ELife 2020, 9 PMID: 32286221, PMCID: PMC7182432, DOI: 10.7554/eLife.53085.
  • β3 adrenergic receptor as potential therapeutic target in ADPKD.Schena G, Carmosino M, Chiurlia S, Onuchic L, Mastropasqua M, Maiorano E, Schena FP, Caplan MJ. β3 adrenergic receptor as potential therapeutic target in ADPKD. Physiological Reports 2021, 9: e15058. PMID: 34676684, PMCID: PMC8531837, DOI: 10.14814/phy2.15058.
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