Kid3 cardiomyocyte3/12/2023 The formation of this BCR signalosome (in which other components also participate) leads to the activation of multiple downstream signaling pathways ( 2). Autophosphorylation on Y223 allows full BTK activation that can then phosphorylate PLCγ2. LYN and SYK also phosphorylate tyrosine residues in the cytoplasmic tail of the B-cell co-receptor CD19 and/or the adaptor protein B-cell PI3K adaptor (BCAP), which facilitates recruitment and activation of PI3K thus reinforcing the signaling that activates BTK. PIP3 binding to BTK N-terminal PH-domain allows its recruitment (in a dimeric form) to the plasma membrane and its subsequent activating phosphorylation by Src-family kinases LYN or SYK on Y551. ![]() In particular, upon engagement of the BCR by a specific antigen, LYN kinase is first recruited at the intracellular portion of the receptor, where it activates SYK that in turn phosphorylates PI3K, thus enabling PIP3 generation. In fact, its activity was found necessary for relaying the signals triggered by the engagement of the B-cell receptor (BCR), thus being involved in the crucial steps of differentiation, proliferation, maturation and survival of B cells. Since the beginning, it has been recognized that BTK plays a pivotal role in B cell physiology. For this reason, BTK has been gaining tremendous momentum in recent years, taking center stage in different biological scenarios and becoming one of the “hottest” actionable targets in several diseases, including cancer. However, the further we go in studying this kinase, the more facets we discover in a protein that once was believed to be one size-fits-it all and hematopoietic-specific. The discovery of the Bruton tyrosine kinase (BTK) as the product of the defective gene in X-linked agammaglobulinemia goes back to almost thirty years ago ( 1). In this perspective we briefly summarize the progress made in the last decade in studying BTK and its isoforms in cancer cells and define the open questions to be addressed in order to get the most benefits from its targeting for therapeutic purposes. Remarkably, the different isoforms appear to be involved in different signaling pathways which will have to be attentively specified in order to define the area of therapeutic intervention. ![]() The growing interests in BTK also led to the discovery that, in solid tumors, two novel isoforms are mainly expressed and actionable liabilities for target therapy. Initial evidence that BTK plays a critical role in B cell-derived malignancies prompted the chase for specific inhibitors, the forefather of which entered the clinic in a record time and paved the way for an ever increasing number of new molecules to be trialed. In the last decade data piled up indicating that BTK – for twenty years considered as a “private matter” of bone marrow-derived cells – it is expressed and plays important and different roles also outside of the hematopoietic compartment and, most notably, in tumor cells. Laboratory of Molecular Medicine, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.Emanuela Grassilli *, Maria Grazia Cerrito and Marialuisa Lavitrano
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