Michael J. Caplan, M.D., Ph.D.

Professor of Cellular & Molecular Physiology and Cell Biology
Caplan lab website Phone: (203) 785-7316 Lab: (203) 785-6833 Fax: (203) 785-4951 e-mail: michael.caplan@yale.edu		Department of Cellular & Molecular Physiology Yale University School of Medicine 333 Cedar Street P.O. Box 208026 New Haven, CT 06520-8026 <Courier Address> 333 Cedar Street, SHM B-116/117 New Haven, CT 06510-3206

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We are interested in the molecular signals and cellular machinery involved in generating epithelial polarity. Membrane proteins whose distributions are restricted to one or the other cell surface domains of polarized cells must contain within their structure information that specifies their appropriate subcellular destinations.

Our studies of these "sorting signals" make use of families of transport proteins, each of whose members are sorted to different surfaces despite extensive homology. This approach has allowed us to identify segments of these molecules that contribute to their sorting behaviors as well as to their physiologic properties. Quite recently we have found that a novel class of membrane proteins, known as the tetraspanins, may play critical roles in the sorting and trafficking of a wide variety of epithelial transport proteins.

Polycystic kidney disease is caused by mutations in genes encoding membrane proteins, polycystin-1 and 2. We have found that polycystin-1 undergoes a proteolytic cleavage that releases its cytoplasmic C terminal tail. This tail fragment undergoes regulated transport to the nucleus, where it appears to modulate several key signaling pathways. This behavior may in part account for the capacity of the polycystin proteins to participate in signaling pathways that communicate between the cell surface and the nucleus.

Selected Publications

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Courtois-Coutry N, Roush DL, Rajendran V, McCarthy JB, Geibel J, Kashgarian M, Caplan MJ. (1997) A Tyrosine-Based Signal Targets H/K-ATPase to a Regulated Compartment and is Required for the Cessation of Gastric Acid Secretion. Cell 90: 501-510.

Roush DL, Gottardi CJ, Naim HY, Roth MG, Caplan MJ. (1998) Tyrosine-Based Membrane Protein Sorting Signals are Differentially Interpreted by Polarized MDCK and LLC-PK1 Epithelial Cells. J Biol Chem. 273: 26862-26869.

Dunbar LA, Aronson PL, Caplan MJ. (2000) A Transmembrane Segment Determines the Steady-State Localization of an Ion Transporting Adenosine Triphosphatase. J Cell Biol. 148: 769-778.

Egan ME, Gloeckner-Pagel J, Ambrose CA, Cahill PA, Papoe L, Balamuth N, Cho E, Canny S, Wagner CA, Geibel J, Caplan MJ. (2002) Calcium-pump inhibitors induce functional surface expression of delta F508-CFTR protein in cystic fibrosis epithelial cells. Nature Medicine 8: 485-492.

Muth TR & Caplan MJ. (2003) Transport Protein Trafficking in Polarized Cells. Ann Rev Cell Dev Biol. 19: 333-366.

Grimm DH, Cai Y, Chauvet V, Rajendran V, Zeltner R, Geng L, Avner ED, Sweeney W, Somlo S, and Caplan MJ. (2003) Polycystin-1 distribution is modulated by polycystin-2 expression in mammalian cells. J Biol Chem., 278: 36786-36793.

Duffield A, Kamsteeg EJ, Brown AN, Pagel P, Caplan MJ. (2003) The tetraspsanin CD63 enhances the internalization of the H,K-ATPase ß-subunit. Proc Nat Acad. Sci. USA 100: 15560-15565.

Egan ME, Pearson M, Weiner SA, Rajendran V, Rubin D, Gloeckner-Pagel J, Canny S, Du K, Lukacs G, Caplan MJ. (2004) Curcumin, a major constitutent of turmeric, corrects cystic fibrosis defects. Science 304: 600-602.

Duffield A, Fölsch H, Mellman I, Caplan MJ. (2004) Sorting of H,K-ATPase ß-subunit in MDCK and LLC-PK1 cells is independent of µ1B adaptin expression. Traffic. 5(6): 449-61.

Chauvet V, Tian X, Husson H, Grimm DH, Wang T, Hieseberger T, Igarashi P, Bennett AM, Ibraghimov-Beskrovnaya O , Somlo S,  Caplan MJ. (2004) Mechanical stimuli induce the cleavage and nuclear translocation of the polycystin-1 C-terminus. J. Clin. Invest. 114: 1433-1443.

Zatti A., Chauvet V, Rajendran V, Kimura T, Pagel P, Caplan MJ. (2005) The C-Terminal Tail of the Polycystin-1 Protein Interacts with the Na,K-ATPase a-Subunit. Mol. Biol. Cell 16:5087-5093.
Grimm D., Karihaloo A, Cai Y, Somlo S, Cantley LG, Caplan MJ. (2006) Polycystin-2 regulates proliferation and branching morphogenesis in kidney epithelial cells. J. Biol. Chem. 281:137-144.

Zhang L, Li J, Young LH, Caplan MJ. (2006) AMP-activated protein kinase regulates the assembly of epithelial tight junctions. Proc. Natl. Acad. Sci. (USA) 103:17272-17277.