Novel roles of ErbB3 receptor tyrosine kinase in vesicular trafficking

Abstract: ErbB3 is a catalytically impaired receptor tyrosine kinase (RTK) from the EGFR family. Upon ligand binding, ErbB3 forms heterodimers with other members of the family and triggers phosphorylation cascades that promote crucial cellular functions as proliferation, differentiation and survival. ErbB3 is also an important player in cancer progression, where it mediates resistance to EGFR inhibitors and promotes metastasis.In this thesis we have identified, first, a role of ErbB3 in promoting vesicular recycling of different cargoes, as β1-Integrin or E-cadherin. Vesicular recycling is the process by which  cargo proteins are internalized and delivered back to the plasma membrane. This process allows fine tuning of the cargoes function, adjusting their availability on the membrane to different conditions. In the case of β1-Integrin, an important adhesion receptor that mediates association of cells with the extracellular matrix, proper recycling is required for cellular adhesion and migration, among other functions. E-cadherin, on the other hand, is the major cell-to-cell junctional molecule in between epithelial cells, and therefore its availability at the plasma membrane is required for the formation and maintenance of epithelial tissues.In addition, we also present the finding that ErbB3 plays a role in exosome release. Exosomes are small extracellular vesicles originated from the fusion of multivesicular bodies with the plasma membrane. Exosomes are crucial for intercellular communication and are able to act as cargo delivery units both under physiological conditions and in the context of disease. Our work shows that ErbB3 inhibits exosome release and dictates their cargo composition, which may have important implications for their function.Finally, we have also investigated novel mechanisms for regulation of ErbB3 function. Therefore, this thesis also includes our work on non-receptor tyrosine kinase Ack1, a multifaceted kinase which has been extensively linked to tumour progression and cancer cell survival. We show for the first time that Ack1 acts as an important negative regulation of ErbB3 protein level.Altogether, this thesis contributes to our understanding of ErbB3 cellular functions and modes of regulation, unveiling new roles of this RTK in vesicular trafficking and exosome release, and proposing Ack1 as a novel modulator of its function.