PI3K – Protein tyrosine kinases



Protein tyrosine kinases and serine-threonine kinases have crucial functions in cell signaling, differentiation, motility, and proliferation. PI3K is the most deregulated pathway in human cancers and an essential regulator of cellular proliferation.

PI3K pathway is activated via oncogenic Ras/receptor tyrosine kinases (RTKs), PTEN loss, or activating mutations in PI3Ks. Moreover, PI3K is one of the most promising pathways for targeted therapies. Thus, many serine-threonine or tyrosine kinases contribute to drug resistance elicited by PI3K inhibition.

Cell Signaling by Protein Tyrosine Kinases

Protein kinases (PKs) are enzymes that transfer the phosphoryl group from ATP (adenosine triphosphate) into an acceptor protein. PKs are classified by substrate specificity and amino acid sequences of catalytic domains. Protein phosphorylation causes activation of signal transduction pathways, which are crucial for many biological processes. The most well- characterized protein kinases in the human genome are protein serine/threonine kinases (STKs) and protein tyrosine kinases (PTKs) [1]. Protein tyrosine kinases have been linked to the development of many human disease states such as cancer. In addition to this, tyrosine kinases play a role in regulation of cell growth, metabolism, differentiation, motility, and death. PTKs  are divided into two main groups; receptor and non-receptor tyrosine kinases (TKs). Receptor TKs (RTKs) are transmembrane proteins, that have catalytic intracellular kinase domain and ligand-binding domain. Non-receptor tyrosine  kinases  (NRTKs) are intracellular cytoplasmic proteins with no transmembrane domains. According to enzymatic activities of both TKs, high levels of tyrosine phosphorylation corresponding to enhanced proliferative state. The first idenditified NRTK is Src family. Src is a proto-oncogene that contributes to cancer progression. Most of NRTKs have N-terminal Src-homology (SH) domains along with C-terminal kinase domain. The SH2 domain enables phosphorylated tyrosine binding  and SH3 domain enables protein-protein interaction. The tyrosine kinases activate via autophosphorylation of tyrosine residues. However, this activation is  firmly regulated. Uncontrolled activation of RTKs leads to defective cell proliferation and cancer. RTKs are activated via dimerization of receptors which is mediated by ligands and leads to trans-phosphorylation of tyrosine in kinase domain.

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Relevance of PI3K Signaling Pathway in Human Cancers

Phosphatidylinositol 3-kinase (PI3K) pathway is one of the most activated signaling pathways in human cancer. Several studies have shown that, PI3K deregulation leads to tumor progression of human cancer. This pathway is also crucial regulator of cell proliferation, survival and motility. PI3K harbors lipid kinase activity and is consisted of a regulatory and catalytic subunits which have heterodimeric structure.

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PI3Ks are classified into three classes; Class I, Class II and Class III PI3Ks. Class I PI3Ks are composed of class IA and class IB enzymes. Activation of class IA PI3Ks occur via receptor tyrosine kinases (RTKs) or G-protein-coupled receptors (GPCRs) [14]. The class IA PI3Ks contain p110 catalytic subunit and a p85 regulatory subunit. PIK3CA, PIK3CB, PIK3CD genes encode p110α, p110β and p110δ catalytic subunit isoforms. PIK3R1, PIK3R2, PIK3R3 encode p85α, p85β and p55γ regulatory subunit isoforms. Also, PIK3R1 encodes alternative splice variants, p55α and p50α. The class IA catalytic subunits have an amino-terminal p85-binding domain (p85 BD), RAS-binding domain (RAS BD), Putative membrane-binding domain; C2, helical domain and carboxyl-terminal kinase catalytic domain. The class IA regulatory subunits have p110 binding domain which is also called inter-Src homology (iSH2) domain in between two Src homology 2 (SH2) domains, Src-homology 3 (SH3) domain and a BCR homology (BH) domain. Whenever p85 binds to p110 via iSH2 domain, catalytic activity of p110 is inhibited. In normal cells, p110α and p110β ubiquitously expressed whereas p110δ is mostly expressed in immune cells.

PI3K Resistance Mechanisms

Activation of the Phosphatidylinositol-3-kinase (PI3K) /AKT/mammalian target of rapamycin (mTOR) signaling axis is important for resistance mechanisms of clinical therapies against human cancers. Previous studies have identified that activated tyrosine kinases or serine/threonine kinases contribute to growth compensation upon PI3K inhibition. In addition to this, p110α is a crucial mediator of RTK signaling. Pharmacological inhibition of the PI3K pathway in cancer cells leads to upregulation of RTKs through feedback loops that circumvent baseline level of PI3K inhibition. These compensatory mechanisms contains FOXO transcription factor along with mitogen-activated protein kinase (MAPK) dependent pathway.

By using isoform specific PI3K inhibitors or pan-PI3K inhibitors to  mimic catalytically inactive versions of p110α/p110β causes growth retardation which is compensated by activation of compensatory mechanisms. BYL719 which is a p110 alpha inhibitor is approved by the FDA (Food and Drug Administration). On the other hand, AZD6482 which is a p110 beta inhibitor is in preclinical evaluation. For that reason, to explicate the primary mechanisms of resistance might be a significant therapeutic approach for oncogenesis.

Overexpression of PIM (Proviral Integration site for Moloney murine leukemic virus) protein kinases are related to therapy resistance in hematological malignancies as well as solid tumors by regulating activation of signaling pathways. PIM kinases are constitutively active serine/threonine kinases that consists of three isoforms, PIM1, PIM2 and PIM3. The PIM1 has identified as a proto-oncogene and induced tumor progression by enhancing cell proliferation/differentiation and inhibiting apoptosis. Previous studies identified that overexpression of PIM1 induce tumorigenesis along with elevated MYC levels. Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is the main regulators for PIM1 gene expression by modulating transcription factors. In conclusion, oncogenic PIM1 regulates cell proliferation and cell survival that might be leading reduction of therapeutic drug efficacy by promoting JAK/STAT signaling pathway in MYC driven cancers.

In addition to this, amplification/overexpression of HER2 in breast cancer cell lines can compensate PI3K/mTOR pathway inhibition via activated MAPK pathway.

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