ROLE OF TEC FAMILY KINASES IN REGULATING MAP KINASES

Open Access
Author:
Khong, Hong-Hanh Minh
Area of Honors:
Immunology and Infectious Disease
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Avery August, Thesis Supervisor
  • James Endres Howell, Honors Advisor
Keywords:
  • Itk
  • Txk
  • MAPK
  • ERK
  • PLC-γ
  • T cell signalling
Abstract:
Itk and Txk are TEC family kinases that are important effectors found downstream of the T cell receptor which are involved in T cell signaling, function, and differentiation. While they appear to share homologous domains towards their carboxy-terminals, these two kinases are differentiated by their N-terminal domain. Txk is characterized by a palmitoylated series of cysteine residues which allows it to be constitutively associated with the plasma membrane. Itk, on the other hand, must be recruited to the plasma membrane via its PH domain upon TCR activation. It is thought that these domains played a role in facilitating the activation of the MAPK pathway by affecting kinase localization. In order to evaluate their differential roles in regulating the MAPK pathway, chimera constructs were generated by swapping the N-terminus of these two kinases. The study determined that Itk and PH-Txk phosphorylate PLC-γ at profoundly higher levels than Txk and Cys-Itk. While Itk may lead to greater levels of ERK phosphorylation than TXK, these differences in MAPK activation were not nearly as significant as those observed for phosphorylated PLC-γ. Additionally, there was no difference between the wild type kinases and their respective chimera constructs in their ability to phosphorylate ERK. Lastly, it was determined that Itk played a role in cell proliferation not only during T cell activation but during resting state as well. Thus, it was determined that the PH domain is critical in facilitating Itk’s function to phosphorylate PLC-γ but not to activate MAPKs; Txk may activate the MAPK pathway via a compensatory mechanism that is independent of PLC-γ and finally, ITK may be important for cell survival and growth during resting state.