Research Interest:
A complete list of our published work is available online at Google Scholar:
https://scholar.google.ca/citations?user=vl3U7kMAAAAJ Research in this laboratory focuses on the area of transmembrane signaling mediated through guanine nucleotide-binding regulatory proteins (G proteins). Many of these signaling pathways are involved in control of cell growth; this property is highlighted by discoveries over the past decade that mutations in or aberrant regulation of G proteins can lead to cell transformation. There are two major areas of research ongoing in the lab.
G Protein Signaling in Oncogenesis and Metastasis G proteins transmit a wide array of extracellular signals from cell surface G protein-coupled receptors (GPCRs) to intracellular effector molecules. One of our focuses is heterotrimeric G proteins in biological function regulations, particularly G12 subfamily. We have found that signaling by the G12 subfamily of G proteins, comprised of GNA12 and GNA13, promotes tumorigenesis and cancer cell invasion. Both GNA12 and GNA13 are upregulated in breast, prostate, gastric and head & neck cancers, and we have shown that blocking GNA12 and GNA13 expression, or their activities, suppresses tumorigenesis and metastasis in multiple cell and animal models. Our most recent finding is that the GNA13 regulatory pathway confers tumor initiation, also referred to as cancer stem cell-like, properties on cancer cells. Our goals in this program are to elucidate the molecular mechanisms of signaling through G12 proteins and determine the impact of targeted inhibition of these processes on oncogenesis and cancer cell metastasis.
Selected references : Meigs, T.E, Fields, T.A., McKee, D.D. & Casey, P.J. (2001) Interaction of Gα12 and Gα13 with the cytoplasmic domain of cadherin provides a mechanism for β-catenin release. Proc. Natl. Acad. Sci. 98:519-524.
Kelly, P., Moeller, B.J., Booden, M.A., Kasbohm, E.A., Madden, J.F., Der, C.J., Daaka, Y, Dewhirst, M.W., Fields, T.A. & Casey, P.J. (2006) The G12 family of heterotrimeric G-proteins promotes cancer invasion and metastasis. Proc. Natl. Acad. Sci. 103:8173-8178.
Juneja, J. & Casey, P.J. (2009) Role of G12 proteins in oncogenesis and metastasis. Brit. J. Pharmacol., 158:32-40.
Kimple, M.E., Moss, J.B, Brar, H.K., Rosa, T.C., Newgard, C.B. & Casey, P.J. (2012) Deletion of Gαz protects against diet-induced glucose intolerance via expansion of β-cell mass. J. Biol. Chem. 287:20344-20355.
Rasheed, S.A.K., Teo, C.R., Beillard, E.J., Voorhoeve, M. & Casey, P.J. (2013) MicroRNA-182 and microRNA-200a control GNA13 expression and cell invasion synergistically in prostate cancer cells. J. Biol. Chem., 288:7986-7995.
Kimple, M.E. Linneman, A.K. & Casey, P.J. (2014) Inhibitory G proteins and their receptors: Emerging therapeutic targets for obesity and diabetes. Exp. Mol. Med., 46:e102.
Rasheed, S.A.K., Teo, C.R., Beillard, E.J., Voorhoeve, M., & Casey, P.J. (2015) MicroRNA-31 controls G protein alpha-13 (GNA13) expression and cell invasion in breast cancer cells. Mol. Cancer 14:67.
Rasheed, S.A.K, Leong, H.S, Lakshmanan, M, Raju, A.K., Dadlani, D., Chong, F.T., Skanthakumar, T., Tan, E.Y., Hwang, J.S., Lim, K.H., Tan, D.S, Tergaonkar, V., Casey, P.J. & Iyer, N.G. (2017) GNA13 expression promotes drug resistance and cancer stem-like phenotypes in solid tumors. Oncogene doi: 10.1038/s41388-017-0038-6. [Epub ahead of print].
Mechanisms and Consequences of Protein Prenylation We have a long-standing program in studying covalent modification of G proteins by isoprenoid lipids and the role this modification, termed protein prenylation, plays in the membrane targeting and function of G proteins, particularly the Ras family of small G proteins. We are studying the enzymes that catalyze these modifications to both define the molecular mechanisms of the processing pathway and to elucidate the role of prenylation in G protein function. The importance of this work is highlighted by the fact that several of these enzymes, most notably protein farnesyltransferase (FTase) and geranylgeranyltransferase (GGTase-1) and a specific methyltransferase termed Icmt have become major targets in the development of anti-cancer therapeutics. Our recent work in this area has been in collaboration with Assoc. Professor Mei Wang in the Cancer and Stem Cell Biology Program.
Selected references: Casey, P.J., Solski, P.A., Der, C.J., and Buss, J.E. (1989) p21ras is modified by a farnesyl isoprenoid. Proc. Natl. Acad. Sci. USA 86:8323-8327.
Casey, P.J., Thissen, J.A. & Moomaw, J.F. (1991) Enzymatic modification of proteins with a geranylgeranyl isoprenoid. Proc. Natl. Acad. Sci. USA 88:8631-8635.
Zhang, F.L. & Casey, P.J. (1996) Protein prenylation: Molecular mechanisms and biological consequences. Ann. Rev. Biochem. 65:241-269.
HW Park, SR Boduluri, JF Moomaw, PJ Casey, LS Beese (1997) Crystal structure of protein farnesyltransferase at 2.25 Å resolution. Science 275:1800-1804.
JC Otto, E Kim, SG Young, PJ Casey (1999) Cloning and characterization of a mammalian prenyl protein-specific protease. J. Biol. Chem. 274 (13), 8379-8382
Long, S.B., Casey, P.J. & Beese, L.S. (2002) Reaction path of protein farnesyltransferase at atomic resolution. Nature 419:645-650.
Winter-Vann, A.M., Baron, R.A., Wong, W., Dela Cruz, J., York, J.D., Gooden, D., Bergo, M.O., Young, S.G., Toone, E.J. & Casey, P.J. (2005) A small molecule inhibitor of isoprenylcysteine carboxylmethyl-transferase with antitumor activity in cancer cells. Proc. Natl. Acad. Sci. 102:4336-4341
Winter-Vann, A.M. & Casey, P.J. (2005) Post-prenylation processing enzymes as targets for development of anti-cancer therapeutics. Nat. Rev. Cancer 5:405-412
Peterson, Y.K., Kelly, P., Weinbaum, C.A., Casey, P.J. (2006) A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity. J. Biol. Chem. 281 (18), 12445-12450
Bailey, C.R., Kelly, P. & Casey, P.J. (2009) Activation of Rap1 promotes prostate cancer metastasis. Cancer Res., 69:4962-4968.
Ullah, N., Mansha1, M. & Casey, P.J. (2016) Protein geranylgeranyltransferase type 1 as a target in cancer. Curr. Cancer Drug Targets 16:563-571.
Wang, M. & Casey, P.J. (2016) Protein prenylation: unique fats make their mark on biology. Nat. Rev. Mol. Cell Biol. 17:110–122.
Lau, H.Y., Tang, J., Casey, P.J. & Wang, M. (2017) Isoprenylcysteine carboxylmethyltransferase is critical for malignant transformation and tumor maintenance by all isoforms of Ras. Oncogene, 36:3934-3942.
Manu, K.A., Chai,T.F., Teh, J.T., Zhu, W.L., Casey, P.J. & Wang, M. (2017) Inhibition of isoprenylcysteine carboxylmethyltransferase induces cell cycle arrest and apoptosis driven by p21 and p21- regulated BNIP3 induction. Mol. Cancer Ther., 16:914-923.
Do, M.T., Chai, T.F., Casey, P.J. & Wang, M. (2017) Isoprenylcysteine carboxylmethyltransferase function is essential for RAB4A-mediated integrin β3 recycling, cell migration and cancer metastasis. Oncogene 36 (41): 5757-5767.
A complete list of our published work is available online at Google Scholar: https://scholar.google.ca/citations?user=vl3U7kMAAAAJ
GNA13 expression promotes drug resistance and cancer stem-like phenotypes in solid tumors.
Rasheed, S.A.K, Leong, H.S, Lakshmanan, M, Raju, A.K., Dadlani, D., Chong, F.T., Skanthakumar, T., Tan, E.Y., Hwang, J.S., Lim, K.H., Tan, D.S, Tergaonkar, V., Casey, P.J.* & Iyer, N.G.* (2017)
Oncogene. Dec 19. doi: 10.1038/s41388-017-0038-6. [Epub ahead of print]
Isoprenylcysteine carboxylmethyltransferase is critical for malignant transformation and tumor maintenance by all isoforms of Ras.
Lau, H.Y., Tang, J., Casey, P.J. & Wang, M. (2017)
Oncogene, 36:3934-3942.
c-Jun contributes to transcriptional control of GNA12 expression in prostate cancer cells.
Kumari, U. & Casey, P.J. (2017)
Molecules 36(27):3934-3942
Isoprenylcysteine carboxylmethyltransferase function is essential for RAB4A-mediated integrin β3 recycling, cell migration and cancer metastasis.
Do, M.T., Chai, T.F., Casey, P.J. & Wang, M. (2017)
Oncogene, 12;36(41):5757-5767.
Inhibition of isoprenylcysteine carboxylmethyltransferase induces cell cycle arrest and apoptosis driven by p21 and p21- regulated BNIP3 induction.
Manu, K.A., Chai,T.F., Teh, J.T., Zhu, W.L., Casey, P.J. & Wang, M. (2017)
Mol. Cancer Ther., 16:914-923.
Protein prenylation: unique fats make their mark on biology.
Wang, M. & Casey, P.J. (2016)
Nat. Rev. Mol. Cell Biol. 17:110–122.
The GNA13-RhoA signaling axis suppresses expression of tumor protective Kallikreins.
Teo, C.R., Casey, P.J. & Rasheed, S.A. (2016)
Cell. Signal. 28:1479-1488
Protein Geranylgeranyltransferase Type 1 as a Target in Cancer.
Ullah, N., Mansha, M. & Casey, P.J. (2016)
Curr Cancer Drug Targets 16:563-571.
MicroRNA-31 controls G protein alpha-13 (GNA13) expression and cell invasion in breast cancer cells.
Rasheed, S.A., Teo, C.R., Beillard, E.J., Voorhoeve, M., & Casey, P.J. (2015)
Mol. Cancer 14:67.
Isoprenylcysteine carboxylmethyltransferase regulates mitochondrial respiration and cancer cell metabolism.
Teh, J.T., Zhu, W., Ilkayeva, Li, Gooding, J, Casey, P.J., Summers, S.A., Newgard, C.B. & Wang, M. (2015)
Oncogene 34:3296-3304.
Breast cancer cell invasion mediated by Gα12 involves expression of IL-6 and IL-8, and matrix metalloproteinase-2.
Chia, C.Y., Kumari, U. & Casey, P.J. (2014)
J. Mol. Signal., 9:6.
Gαz regulates BDNF-induction of axon growth in cortical neurons.
Hultman, R., Kumari, U., Michel, N. & and Casey, P.J. (2014)
Mol. Cell. Neuro. 58:53-61.
Inhibitory G proteins and their receptors: Emerging therapeutic targets for obesity and diabetes.
Kimple, M.E. Linneman, A.K. & Casey, P.J. (2014)
Exp. Mol. Med., 46:e102.
MicroRNA-182 and microRNA-200a control GNA13 expression and cell invasion synergistically in prostate cancer cells.
Rasheed, S.A., Teo, C.R., Beillard, E.J., Voorhoeve, M. & Casey, P.J. (2013)
J. Biol. Chem, 288:7986-7995.
Deletion of Gαz protects against diet-induced glucose intolerance via expansion of β-cell mass.
Kimple, M.E., Moss, J.B, Brar, H.K., Rosa, T.C., Newgard, C.B. & Casey, P.J. (2012)
J. Biol. Chem. 287:20344-20355.
Role of G12 proteins in oncogenesis and metastasis.
Juneja, J. & Casey, P.J. (2009)
Brit. J. Pharmacol., 158:32-40.
Activation of Rap1 promotes prostate cancer metastasis.
Bailey, C.R., Kelly, P. & Casey, P.J. (2009)
Cancer Res., 69:4962-4968.
Gαz negatively regulates insulin secretion and glucose clearance.
Kimple,M.E., Joseph, J.W., Bailey, C.L., Fueger, P.T., Hendry, I.A., Newgard, C.B. & Casey, P.J. (2008)
J. Biol. Chem. 283:4560-4567.
A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity.
Peterson, Y.K., Kelly, P., Weinbaum, C.A., Casey, P.J. (2006)
J. Biol. Chem. 281 (18), 12445-12450
The G12 family of heterotrimeric G-proteins promotes cancer invasion and metastasis.
Kelly, P., Moeller, B.J., Booden, Der, C.J., Daaka, Y, Dewhirst, M.W., Fields, T.A. & Casey, P.J. (2006)
Proc. Natl. Acad. Sci. 103:8173-8178.
Post-prenylation processing enzymes as targets for development of anti-cancer therapeutics.
Winter-Vann, A.M. & Casey, P.J. (2005)
Nature Rev Cancer 5:405-412
A small molecule inhibitor of isoprenylcysteine carboxylmethyltransferase with antitumor activity in cancer cells.
Winter-Vann, A.M., Baron, R.A., Wong, W., Dela Cruz, J., York, J.D., Gooden, D., Bergo, M.O., Young, S.G., Toone, E.J. & Casey, P.J. (2005)
Proc. Natl. Acad. Sci. 102:4336-4341
Reaction path of protein farnesyltransferase at atomic resolution.
Long, S.B., Casey, P.J. & Beese, L.S. (2002)
Nature 419:645-650.
Interaction of Ga12 and Ga13 with the cytoplasmic domain of cadherin provides a mechanism for β-catenin release.
Meigs, T.E, Fields, T.A., McKee, D.D. & Casey, P.J. (2001)
Proc. Natl. Acad. Sci. 98:519-524.
The basis for K-Ras4B binding specificity to protein farnesyl-transferase revealed by 2 Å resolution ternary complex structures
SB Long, PJ Casey, LS Beese (2000)
Structure 8 (2), 209-222
Cloning and characterization of a mammalian prenyl protein-specific protease.
JC Otto, E Kim, SG Young, PJ Casey (1999)
J. Biol. Chem. 274 (13), 8379-8382
Cocrystal structure of protein farnesyltransferase complexed with a farnesyl diphosphate substrate.
SB Long, PJ Casey, LS Beese (1998)
Biochemistry 37 (27), 9612-9618
Crystal structure of protein farnesyltransferase at 2.25 Å resolution.
HW Park, SR Boduluri, JF Moomaw, PJ Casey, LS Beese. (1997)
Science 275:1800-1804.
Protein prenylation: Molecular mechanisms and biological consequences.
Zhang, F.L. & Casey, P.J. (1996)
Annu. Rev. Biochem. 65:241-269.
Enzymatic modification of proteins with a geranylgeranyl isoprenoid.
Casey, P.J., Thissen, J.A. & Moomaw, J.F. (1991)
Proc. Natl. Acad. Sci. USA 88:8631-8635
Mammalian protein geranylgeranyltransferase. Subunit composition and metal requirements.
JF Moomaw, PJ Casey (1992)
J. Biol. Chem. 267 (24), 17438-17443
Enzymatic modification of proteins with a geranylgeranyl isoprenoid.
PJ Casey, JA Thissen, JF Moomaw (1991)
Proc. Natl. Acad. Sci. 88 (19), 8631-8635
p21ras is modified by a farnesyl isoprenoid.
PJ Casey, PA Solski, CJ Der, JE Buss, J.E.
Proc. Natl. Acad. Sci. USA 86:8323-8327