Our long-term goal is to understand the mechanisms by which epithelial cells develop structural and functional asymmetry. This process is critical to the normal function of epithelial tissues and loss of epithelial polarity is associated with a variety of human pathologies including cancers, cystic diseases, secretory and absorptive disorders and cardiovascular disease. An evolutionarily conserved event in cell polarization involves cortical capture and selective stabilization of MTs. In stabilizing a subset of MTs selectively, cells develop an axis of morphological asymmetry along which local signals are transduced and on which MT motor proteins carry diverse cargoes to and from specific domains inside and on the surface of cells. While it is known that signaling from specific cortical sites triggers the local MT reorganization necessary for polarization, the molecules and regulatory mechanisms orchestrating these processes have not been elucidated fully. Recently, we obtained evidence implicating a member of the kinesin family of MT motors in polarization of epithelial cells. Interestingly, this kinesin localizes to MT plus-ends and to the cell cortex where it interacts with well- characterized MT plus-end associated proteins and cortical membrane-cytoskeletal scaffolding proteins. This suggests that the kinesin is involved in cortical capture and stabilization of MTs. Based on analogy with polarization mechanisms in single-cell organisms, we hypothesize that this kinesin acts as a selective transporter of factors regulating MT stabilization and cell polarity in epithelia. However, the relevant cargoes transported by this motor that could promote MT stabilization and cell polarity are still unknown. We will test our hypothesis by identifying epithelial cargoes of KIF17 and testing whether they too regulate epithelial polarization. In addition, we will characterize the mechanism by which this kinesin and its cargoes regulate cell polarity. Another important process in epithelial polarization involves the selective and targeted transport of membrane and secreted proteins to different regions of the cell surface. However, little is known about how cellular cargoes select appropriate motor(s) to get them to the correct destination and how motors identify appropriate routes to these destinations. We showed recently the existence of polarization-dependent, """"""""kinesin-switching"""""""" by an apical membrane protein cargo being transported from the Golgi to the plasma membrane. This leads us to hypothesize that kinesin interactions with specific cargoes are regulated during epithelial polarization. This kinesin-cargo switch likely facilitates development of functional membrane asymmetry in response to MT reorganization. To test this idea we will identify proteins that regulate the binding of kinesin to vesicles containing the apical membrane protein p75. We will then characterize how kinesin- vesicle interactions are regulated during epithelial polarization. Understanding the role of kinesins in epithelial polarization may provide critical new information about how this process is controlled and could lead to identification of novel therapeutic targets in treating diseases of epithelial origin.

Public Health Relevance

Polarized epithelial cells play a key role in maintaining internal homeostasis by acting as a barrier between the outside environment and internal organs. Our long-term goal is to understand, at molecular and mechanistic levels, how epithelial cells develop structural and functional asymmetry, a process critical to the normal function of tissues comprised of these cells. Indeed, loss of epithelial polarity is associated with a variety of human pathologies including cancers of diverse tissue origin, cystic diseases and mal-absorption and secretory disorders in several organ systems. Elucidation of molecular events driving polarization is important, not only for understanding normal development, but also because the details of this process will enable us to develop therapeutic intervention strategies targeting diseases associated with loss of epithelial polarity.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CB-J (03))
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Gindhart, Joseph G
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Weill Medical College of Cornell University
Anatomy/Cell Biology
Schools of Medicine
New York
United States
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Seneviratne, Am Pramodh Bandara; Turan, Zeynep; Hermant, Aurelie et al. (2017) Modulation of estrogen related receptor alpha activity by the kinesin KIF17. Oncotarget 8:50359-50375
Acharya, Bipul R; Espenel, Cedric; Libanje, Fotine et al. (2016) KIF17 regulates RhoA-dependent actin remodeling at epithelial cell-cell adhesions. J Cell Sci 129:957-70
Xing, Bowen; Wang, Limin; Guo, Dagang et al. (2013) Atypical protein kinase C? is critical for growth factor receptor-induced dorsal ruffle turnover and cell migration. J Biol Chem 288:32827-36
Espenel, Cedric; Acharya, Bipul R; Kreitzer, Geri (2013) A biosensor of local kinesin activity reveals roles of PKC and EB1 in KIF17 activation. J Cell Biol 203:445-55
Acharya, Bipul R; Espenel, Cedric; Kreitzer, Geri (2013) Direct regulation of microtubule dynamics by KIF17 motor and tail domains. J Biol Chem 288:32302-13
Nekrasova, Oxana E; Amargo, Evangeline V; Smith, William O et al. (2011) Desmosomal cadherins utilize distinct kinesins for assembly into desmosomes. J Cell Biol 195:1185-203
Xue, Xiaoxiao; Jaulin, Fanny; Espenel, Cedric et al. (2010) PH-domain-dependent selective transport of p75 by kinesin-3 family motors in non-polarized MDCK cells. J Cell Sci 123:1732-41
Jaulin, Fanny; Kreitzer, Geri (2010) KIF17 stabilizes microtubules and contributes to epithelial morphogenesis by acting at MT plus ends with EB1 and APC. J Cell Biol 190:443-60