Carol L. Williams, PhD
Joan K. Van Deuren Professor in Breast Cancer Research; Leader, Cancer Biology Research Program, Cancer Center; Professor, Pharmacology & Toxicology
- Pharmacology and Toxicology
Our research focuses on the biochemical signaling pathways and cellular processes regulated by the Ras and Rho families of small GTPases. These proteins regulate important physiological processes in a variety of cell types, including cell proliferation and migration. Abnormal signaling by these proteins contributes to several diseases, including cancer and cardiovascular disease. The importance of these proteins in human health provides the driving force for our studies.
Regulation of small GTPases by the chaperone protein SmgGDS (gene name RAP1GDS1)
SmgGDS is a chaperone protein that binds multiple members of the Ras and Rho families, including K-Ras, Rap1, RhoA, and Rac1. We found that SmgGDS regulates the contraction and migration of vascular smooth muscle cells by activating the small GTPase RhoA, indicating that SmgGDS may be an important participant in diseases involving abnormal contraction and migration of vascular smooth muscle cells, such as hypertension and atherosclerosis. We also found that SmgGDS expression is elevated in several types of cancer and is needed for cancer cells to proliferate and migrate, indicating that SmgGDS is an important regulator of tumorigenesis and metastasis.
We recently discovered that there are two functionally distinct splice variants of SmgGDS, which we named SmgGDS-607 and SmgGDS-558, based on the number of amino acids in each protein. We found that these SmgGDS splice variants participate in signaling pathways that regulate the prenylation of small GTPases. Prenylation is the covalent attachment of an isoprenyl group (farnesyl or geranylgeranyl) to the C-terminus of the small GTPase. This post-translational modification increases the association of small GTPases with cell membranes, where small GTPases are believed to be most active. Our studies indicate that SmgGDS-607 regulates the entry of non-prenylated small GTPases into the prenylation pathway, whereas SmgGDS-558 promotes the trafficking of prenylated small GTPases to cell membranes. These different functions of SmgGDS splice variants provide a previously unsuspected mechanism to control small GTPase prenylation and localization. The participation of SmgGDS splice variants in the prenylation pathway explains how SmgGDS can regulate the activities of so many different small GTPases. We are currently examining how SmgGDS splice variants interact with different small GTPases to regulate their prenylation and trafficking. These studies will further define the unique roles of SmgGDS in cancer and cardiovascular disease.
Nuclear localization signals in members of the Ras and Rho families of small GTPases
A major goal of our research is to understand how small GTPases regulate the cytoskeletal organization, contraction, migration, and proliferation of mammalian cells. It is generally accepted that members of the Ras and Rho families regulate these critical cellular functions by interacting with proteins found in the cytoplasm or at cellular membranes. However, we discovered that some members of the Rho family enter the nucleus, where these proteins may regulate nuclear functions. A specific amino acid sequence called the "nuclear localization signal" (NLS) is required for many proteins to enter the nucleus. We observed that NLS sequences are present in the C-terminal region of Rac1 and potentially other Ras and Rho family members, and are evolutionarily conserved across several phyla. We found that Rac1 uses its C-terminal NLS to undergo nucleocytoplasmic shuttling, which is a previously unsuspected function of small GTPases. The NLS may be required for the nuclear entry of small GTPases when they are associated with other proteins in complexes that are too large to passively diffuse through nuclear pores. The nuclear entry of small GTPases may allow signals that are generated in the cytoplasm to be sensed in the nucleus. This ability to enter the nucleus expands the number of signaling pathways that are potentially regulated by these small GTPases, and may explain how these proteins can participate in a wide range of both normal and abnormal cellular responses.
Structural and biophysical properties of farnesylated KRas interacting with the chaperone SmgGDS-558.
(Michalak DJ, Unger B, Lorimer E, Grishaev A, Williams CL, Heinrich F, Lösche M.) Biophys J. 2022 Oct 04;121(19):3684-3697 PMID: 35614853 PMCID: PMC9617131 SCOPUS ID: 2-s2.0-85131506379 05/27/2022
Rap1A, Rap1B, and β-Adrenergic Signaling in Autologous HCT: A Randomized Controlled Trial of Propranolol.
(Johnson AK, Lorimer EL, Szabo A, Wu R, Shah NN, D'Souza A, Chhabra S, Hamadani M, Dhakal B, Hari P, Rao S, Carlson K, Williams CL, Knight JM.) Yale J Biol Med. 2022 Mar;95(1):45-56 PMID: 35370486 PMCID: PMC8961707 SCOPUS ID: 2-s2.0-85127524780 04/05/2022
The complex, dynamic SpliceOme of the small GTPase transcripts altered by technique, sex, genetics, tissue specificity, and RNA base editing.
(Das AS, Sherry EC, Vaughan RM, Henderson ML, Zieba J, Uhl KL, Koehn O, Bupp CP, Rajasekaran S, Li X, Chhetri SB, Nissim S, Williams CL, Prokop JW.) Front Cell Dev Biol. 2022;10:1033695 PMID: 36467401 PMCID: PMC9714508 12/06/2022
SmgGDS: An Emerging Master Regulator of Prenylation and Trafficking by Small GTPases in the Ras and Rho Families.
(Brandt AC, Koehn OJ, Williams CL.) Front Mol Biosci. 2021;8:685135 PMID: 34222337 PMCID: PMC8242357 07/06/2021
Splice switching an oncogenic ratio of SmgGDS isoforms as a strategy to diminish malignancy.
(Brandt AC, McNally L, Lorimer EL, Unger B, Koehn OJ, Suazo KF, Rein L, Szabo A, Tsaih SW, Distefano MD, Flister MJ, Rigo F, McNally MT, Williams CL.) Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3627-3636 PMID: 32019878 PMCID: PMC7035473 SCOPUS ID: 2-s2.0-85079538992 02/06/2020
Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer.
(Nissim S, Leshchiner I, Mancias JD, Greenblatt MB, Maertens O, Cassa CA, Rosenfeld JA, Cox AG, Hedgepeth J, Wucherpfennig JI, Kim AJ, Henderson JE, Gonyo P, Brandt A, Lorimer E, Unger B, Prokop JW, Heidel JR, Wang XX, Ukaegbu CI, Jennings BC, Paulo JA, Gableske S, Fierke CA, Getz G, Sunyaev SR, Wade Harper J, Cichowski K, Kimmelman AC, Houvras Y, Syngal S, Williams C, Goessling W.) Nat Genet. 2019 Sep;51(9):1308-1314 PMID: 31406347 PMCID: PMC7159804 SCOPUS ID: 2-s2.0-85070822684 08/14/2019
SmgGDS is a transient nucleolar protein that protects cells from nucleolar stress and promotes the cell cycle by regulating DREAM complex gene expression.
(Gonyo P, Bergom C, Brandt AC, Tsaih SW, Sun Y, Bigley TM, Lorimer EL, Terhune SS, Rui H, Flister MJ, Long RM, Williams CL.) Oncogene. 2017 Dec 14;36(50):6873-6883 PMID: 28806394 PMCID: PMC5730474 SCOPUS ID: 2-s2.0-85038242723 08/15/2017
The Nogo-B receptor promotes Ras plasma membrane localization and activation.
(Zhao B, Hu W, Kumar S, Gonyo P, Rana U, Liu Z, Wang B, Duong WQ, Yang Z, Williams CL, Miao QR.) Oncogene. 2017 Jun 15;36(24):3406-3416 PMID: 28068323 PMCID: PMC5472485 SCOPUS ID: 2-s2.0-85008618992 01/10/2017
Differences in the Phosphorylation-Dependent Regulation of Prenylation of Rap1A and Rap1B.
(Wilson JM, Prokop JW, Lorimer E, Ntantie E, Williams CL.) J Mol Biol. 2016 Dec 04;428(24 Pt B):4929-4945 PMID: 27760305 PMCID: PMC5153279 SCOPUS ID: 2-s2.0-85000398931 10/21/2016
The tumor-suppressive small GTPase DiRas1 binds the noncanonical guanine nucleotide exchange factor SmgGDS and antagonizes SmgGDS interactions with oncogenic small GTPases.
(Bergom C, Hauser AD, Rymaszewski A, Gonyo P, Prokop JW, Jennings BC, Lawton AJ, Frei A, Lorimer EL, Aguilera-Barrantes I, Mackinnon AC Jr, Noon K, Fierke CA, Williams CL.) J Biol Chem. 2016 May 13;291(20):10948 PMID: 27197236 PMCID: PMC4865938 05/20/2016
The Tumor-suppressive Small GTPase DiRas1 Binds the Noncanonical Guanine Nucleotide Exchange Factor SmgGDS and Antagonizes SmgGDS Interactions with Oncogenic Small GTPases.
(Bergom C, Hauser AD, Rymaszewski A, Gonyo P, Prokop JW, Jennings BC, Lawton AJ, Frei A, Lorimer EL, Aguilera-Barrantes I, Mackinnon AC, Noon K, Fierke CA, Williams CL.) J Biol Chem. 2016 Mar 18;291(12):6534-45 PMID: 26814130 PMCID: PMC4813585 SCOPUS ID: 2-s2.0-84964859354 01/28/2016
β-Adrenergic receptors suppress Rap1B prenylation and promote the metastatic phenotype in breast cancer cells.
(Wilson JM, Lorimer E, Tyburski MD, Williams CL.) Cancer Biol Ther. 2015;16(9):1364-74 PMID: 26209110 PMCID: PMC4622671 SCOPUS ID: 2-s2.0-84941806664 07/26/2015