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Chris Yun, PhD

Lab Personnel

Peijian He, PhD (postdoctoral fellow)
Seijung Lee, PhD (postdoctoral fellow)
Songbai Lin, MD (postdoctoral fellow)
Yi Ran No (research specialist, lead )
Byong Yoo, Ph.D. (postdoctoral fellow

About the Lab

The overall theme of research in our laboratory is the molecular and cellular mechanisms of signal transduction in the intestinal epithelial cells. Our focuses are on two premises. First, understanding the mechanisms of regulation of Na+/H+ exchanger NHE3 and, second, elucidating the role of lysophosphatidic acid (LPA) in modulating intestinal epithelial cells and colon cancer.

 (1) Acute diarrhea is an unpleasant digestive disorder that affects nearly everyone at one time or another. Diarrhea is caused by a decrease in net salt and fluid absorption, which can result from either a decrease in salt absorption or an increase in anion secretion, or both. The major pathway for sodium and water absorption in the intestine is thought involve Na+/H+ exchanger type 3 (NHE3) in the brush border membrane of enterocytes where it acts in concert with an anion exchanger to mediate electroneutral NaCl absorption.

NHE3 is regulated by many factors, including bacterial toxins, steroids, insulin, cytokines, and osmotic stress. The precise mechanisms underlying the regulation of NHE3 are still under investigation, but emerging themes include transcriptional regulation, changes in phosphorylation of NHE3 proteins, and trafficking of NHE3 protein between the brush border membrane and the subapical pool. One mechanism of NHE3 regulation that has been highlighted in recent years is the interaction with Na+/H+ exchanger regulatory factors, NHERF1, NHERF2, and PDZK1, which collectively raised the novel paradigm that the activity of NHE3 can be controlled by its state of association with other cellular proteins. We are studying NHE3 regulation by at least 3 agonist, glucocorticoids, LPA, and calcium.

proteinApart from the well-known effects in metabolism, inflammation, and cardiovascular processes, glucocorticoids are a major hormone stimulating NHE3 via multiple pathways. Our lab has shown that activation of NHE3 by glucocorticoids involves the serum and glucocorticoid-inducible kinase I (SGK1) and NHERF2, and subsequent phosphorylation of NHE3 by SGK1.

Our recent study shows that LPA activate NHE3 and NHE3-dependent fluid absorption in the intestine. Our study involves identification of LPA receptor subtypes and the molecular and cellular mechanisms by which NHE3 is activated by LPA.

The calcium ion (Ca2+) is a highly versatile second messenger that can regulate many different cellular functions. We recently identified IP3 receptor binding protein released with IP3 (IRBIT) as a NHE3 interacting protein and demonstrated its role in regulation of NHE3 activity. We are continuing our effort to elucidate the role of IRBIT in NHE3 regulation by calcium and angiotensin.

(2) LPA is an extracellular lipid mediator that evokes multiple growth factor-like effects in almost every cell type. LPA mediates its effect primarily by coupling to a family of G protein-coupled receptors; LPA1%7eLPA5. The initial indication that LPA could contribute to tumorigenesis came from studies showing that LPA increases cell proliferation and motility, but the findings that LPA is generated by the lysophospholipase D activity of tumor-promoting autotoxin along with an increased LPA concentration in ovarian cancer ascites have heightened its potential role in tumorigenesis. Recent evidence shows that deregulation of LPA2 is commonly found in several types of cancer, including ovarian and colon cancer. On the other hands, LPA1 expression is cellsdecrease in many types of cancer, suggesting that there is imbalance in LPA-mediated signaling in cancer cells.

Our study using colon cancer cells showed that LPA acting on LPA2 mediate mitogenic signals that promote cell proliferation, cytokine induction, and protection of cancer cells from apoptosis. Recently, we showed that mice deficient in LPA2 expression (LPA2-/-) are protected from colitis-associated colon cancer induced by DSS and azoxymethane. The reduced tumor progress in LPA2-/- mice correlates with decreased MCP-1 and MIF induction, and macrophage infiltration. We are continuing our investigation of LPA2-mediated signaling in colon cancer progression and the regulation of LPA2 function via its interaction with PDZ proteins such as NHERF2 and MAGI-3.

Recent Publications

  1. Yun, C.C., Sun, H., Wang,, W., Rusovici, R., Castleberry, A., Hall, R, and Shim, H. (2005) The LPA2 receptor mediates mitogenic signals in human colon cancer cells  Am J. Physiol-Cell. 289:C2-C11
  2. 2. Wang, D., Sun, H., Lang, F., and Yun, C.C. (2005) Activation of NHE3 by dexamethasone requires phosphorylation of NHE3 at S663 by SGK1. Am J. Physiol-Cell. 289: C802-810.
  3. 3. Wang, D., Lee, H., Cebotaro, L., Walden, P.D., Choi, I., and Yun, C.C. (2006) Inhibition of Na+/H+ exchanger NHE3 by microtubule-associate serine/threonine kinase-205. Am. J. Physiol-Renal. 290: F428-F437.
  4. 4. Hryciw DH, Ekberg J, Ferguson C, Lee A, Wang D, Parton RG, Pollock CA, Yun CC, Poronnik P. (2006) Regulation of albumin endocytosis by PSD95/Dlg/ZO-1(PDZ) scaffolds: Interaction of Na+-H+ exchange regulatory factor-2 (NHERF2) with ClC-5. J. Biol. Chem. 281:16068-16077.
  5. 5. Zhang, H, Wang, D, Sun, H, Hall, R.A., and Yun, C.C.  (2007) MAGI-3 regulates LPA-induced activation of ERK and RhoA, Cell. Signal. 9:261-268.
  6. 6. Wang, D., Zhang, H., Lang, F., and Yun, C.C. (2007) Acute activation of Na+/H+ exchanger NHE3 by glucocorticoids correlates with activation of SGK1 and is independent of glucocorticoid receptor Am. J. Physiol-Cell Physiol, 292:C396-404
  7. 7. Zhang, H., Bialkowska, A., Rusovici, R., Chanchevalap, S., Shim, H., Katz, J.P., Yang, V.W., and Yun, C.C. (2007) Lysophosphatidic acid facilitates proliferation of colon cancer cells via induction of Krüppel-like factor 5. J. Biol. Chem. 282:15541- 15549
  8. 8. Rusovici, R., Ghaleb, A.M., Shim, H, Yang, V.W., and Yun, C.C. (2007) Lysophosphatidic acid prevents apoptosis of Caco-2 colon cancer cells via activation of mitogen-activated protein kinase and phosphorylation of Bad. Biochim. Biophys. Acta, 1770:1194-1203.
  9. 9. He, P., Zhang, H., and Yun, C.C. (2008) IRBIT, IP3 receptor binding protein released with IP3, binds Na+/H+ exchanger NHE3 and activates NHE3 activity in response to calcium. J. Biol. Chem. 283:33544-33553.
  10. 10. Singh AK, Riederer B, Krabbenhöft A, Rausch B, Bonhagen J, Lehmann U, de Jonge HR, Donowitz M, Yun C, Weinman EJ, Kocher O, Hogema BM, Seidler U. (2009) Differential roles of NHERF1, NHERF2, and PDZK1 in regulating CFTR-mediated intestinal anion secretion in mice. J. Clin. Invest. 119: 540-550.
  11. 11. Lin, S., Wang, D., Iyer, S., Ghaleb, A.M., Shim, H., Yang, V.W., Chun, J., and Yun, C.C. (2009) LPA2 promotes tumor formation in an experimental model of colitis-associated colon cancer. Gasteroenterology, 136: 1711-1720.