Truncated Trk receptor isoforms lacking the kinase domain are abundantly expressed during development and in the adult;however, their function and signaling capacity is largely unknown. Interestingly, the cytoplasmic tail of the neurotrophin-3 (NT3) truncated TrkCT1- receptor is highly conserved among species, suggesting the potential for important functions in vivo. We have recently shown that NT3 interaction with TrkCT1 activates Arf6-Rac1 signaling through the scaffold protein Tamalin. We found that TrkCT1 binds also the Tamalin homolog Cybr, a scaffold protein highly expressed in the immune system. NT3 treatment of the EL4 lymphoma cell line that express endogenously both TrkCT1 and Cybr, induces intracellular re-localization of Cybr. Since Cybr is involved in pro-inflammatory cytokine-modulated cell migration, our results suggest that TrkCT1 may modulate the recruitment and migration of specific leukocyte cell populations. Indeed, in mouse in which we have deleted Cybr we find specific deficits in blood circulating leukocytes and lymphocytes present in the lymph nodes. Moreover, in a Th1-polarized-mouse model, lymphocyte trafficking is impaired by loss of Cybr and Cybr-deficient mice with aseptic peritonitis have fewer cells than controls present in the peritoneal cavity and fewer leukocytes leaving the blood stream. Mutant mice injected with Moloney-murine sarcoma/leukemia virus develop significantly larger tumors than wild type mice and have reduced lymph node enlargement suggesting reduced cytotoxic T lymphocytes migration. Taken together, these data support a role for Cybr in leukocyte trafficking, especially in response to pro-inflammatory cytokines in stress conditions. We are now investigating which of these Cybr functions are affected by NT-3/TrkC.T1. In a separate project we have investigated whether TrkB Receptors have other functions outside the nervous system. Surprisingly, we found that these receptors control contraction and long-term homeostasis of the mammalian heart. For example, BDNF increases the cardiac contraction force and calcium release in cardiomyocytes through TrkB.T1 and mice lacking TrkB.T1-/- mice show cardiac hypertrophy, calcium channel alteration, dilated cardiomyopathy and reduced heart performances. Together these data suggest that impairment in BDNF/TrkB.T1 signaling can contribute to the etiology of cardiomyopathies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010391-14
Application #
8763094
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2013
Total Cost
$834,125
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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