The focus of my research program is to elucidate fundamental cell biological mechanisms underlying intracellular membrane trafficking and how these mechanisms are usurped by human pathogens and disease processes. One of the major efforts in my laboratory has been to gain fundamental new insights into the nature of polarized EGF receptor (EGFR) trafficking pathways that govern epithelial cell functions and how these pathways are co-opted to dismantle epithelial cell architecture during the genesis of epithelial carcinomas. My laboratory has had the leading role in identifying mechanisms for regulation of the basolateral expression of the EGFR in polarized epithelia leading to development of multiple cell lines with defective EGFR sorting to be employed in these studies. More recently, we have applied our knowledge of EGFR biology to unraveling the role of this molecule in tumor progression in triple-negative breast cancer and have now developed methods for translating our results from tissue culture cells to in situ tumor development.
Membrane trafficking is essential for transport of proteins and other macromolecules to various destinations inside and outside of the cell. Membrane trafficking also underlies the fundamental need for cells to maintain cellular homeostasis, as well as to meet specific demands during cell signaling. These processes are often perturbed in human disease and by viral pathogens.
We study several different aspects of membrane trafficking in mammalian cells. (A) Receptor tyrosine kinase signaling is tightly regulated by endocytosis and post-endocytic sorting. The EGF receptor (EGFR) is a member of the ErbB family that is normally targeted for degradation in lysosomes following ligand stimulation. Other ErbBs that are endocytosis-impaired inhibit EGFR trafficking when they are overexpressed, leading to hyperproliferation and cancer. (B) EGFR is also activated by integrin engagement independent of ligand. Integrin-EGFR interactions control cell migration by inducing formation of membrane protrusions called lamellipodia and filopodia. We have discovered EGFR-dependent signaling pathways that control the types of membrane protrusions that form during cell adhesion which recapitulates the earliest stages of cell migration. Some of these pathways are perturbed in human cancers, providing a potential link between EGFR and deregulated cell migration in tumor microenvironments. (C) Regulation of cholesterol homeostasis by the endomembrane system. We study a membrane protein encoded by human adenovirus that maintains cellular homeostasis by regulating cholesterol transport from endosomes to other parts of the cell. The adenovirus protein compensates for loss-of-function of the NPC1 cholesterol transport protein in cells from patients with Niemann-Pick type C disease, a fatal childhood neuropathy with many similarities to Alzheimer’s disease. (D) Regulation of polarized secretion in renal epithelial cells. Cell polarity is maintained by targeting and retention of proteins to functionally distinct apical and basolateral plasma membrane domains. EGFR, which is normally basolateral, appears on the apical surface in cystic cells from patients with Polycystic Kidney Disease (PKD) where it is a significant disease progression factor. A latent EGF receptor sorting pathway that we recently discovered, which eliminates apical EGFR in cystic cells, represents a potentially new therapeutic target for patients with this debilitating disease.
Cianciola, N.L. and Carlin, C.R. 2010. Adenovirus RIDα protein reveals novel autophagic mechanism that regulates cholesterol homeostasis. Autophagy 6: 296-298. [PubMed]
Cianciola, N.L. and Carlin, C.R. 2009. Adenovirus RIDa activates an autonomous endosomal cholesterol egress mechanism that rescues lipid sorting defects in Niemann-Pick type C disease. J, Cell Biol.187: 537-552. [PubMed] Featured on November 16th Edition of Biobytes, Rockefeller University Press.
Hake, M.J., Choowongkomon, K,, Kostenko, O., Carlin, C.R, and Sönnichsen, F.D. 2008. Specificity determinants of a novel Nck interaction with the juxtamembrane domain of the epidermal growth factor receptor. Biochemistry 47:3096-108. [PubMed]
Shah, AH, Cianciola, NL, Mills, JL, Sönnichsen, FD, and Carlin, CR. 2007. Adenovirus RIDa regulates endosome maturation by mimicking GTP-Rab7. J. Cell Biol. 179:965-980. [PubMed]
Cianciola, N.L., Crooks, D.M., and Carlin, C.R. 2007. A tyrosine-based signal plays a critical role in targeting and function of adenovirus RIDa protein that regulates EGF receptor stability. J. Virology 81:10437-10450. [PubMed]
Kostenko, O., Tsacoumangos, A., Crooks, D., Kil, S.J., and Carlin, C.R. 2006. Gab1 signaling is regulated by EGF receptor sorting in early endosomes. Oncogene 25: 6604-6617 [PubMed]