What is phosphorylation cascade

The processes of phosphorylation and dephosphorylation can be etremely complex, since a single kinase or phosphatase may simultaneously have more substrates and may function in various cell signaling pathways. MAPK is a known protein involved in a signaling pathway activated by a cascade effect of phosphorylation events This complex phosphorylates Stat1, leading to its dimerization and nuclear translocation, where it regulates gene transcription 62 — Therefore, phospho-signaling networks represent the basis of many cellular processes.

They consist mainly of protein kinases, phosphatases, and their respective substrates phospho-binding proteins 66 Fig. There is also a mechanism of competition for kinases and phosphatases at the level of protein sites to adjust the states of phosphorylation of common substrates 67 , PhosphoNET and PhosphoSitePlus websites document the inhibition or activation of human protein with more than different phosphosites with predictions for over 1, additional sites.

Therefore, it is customary to classify phosphorylation into two categories: one refers to functional changes stable and the other one, transitory, has no effect on regulatory functions. For this reason, it is thought that all stable phosphosites are functional and those not stable, are not functional 69 — In addition, the functional effects of phosphosites within a protein are site-dependent 72 , and this means that they are functional only if phosphorylation takes place on a specific site and not random.

This endorses the view that the detailed study of phosphorylation networks may help to understand the physiological and pathological mechanisms 72 — Phosphorylation is one of the most common PTMs involved in the regulation of multiple biological processes and overexpression of kinase. Mutations or defects in regulatory mechanisms can lead to aberrant activation or dysregulation of kinase signaling pathways 77 and this is the basis of oncogenesis for multiple tumors 78 — Cancer is not only considered a disease that arises from genetic mutations, but also a disease that results from epigenetic changes 81 — 83 that mainly lead to a deregulation of signal transduction pathways with subsequent changes in normal cellular mechanisms Many key regulatory proteins controlling gene expression are targets of kinases.

The addition of a phosphate group to a protein by a kinase can alter the activity of the protein and this action is often exploited as a switch on or off 85 , In chronic myeloid leukemia, a particular chromosomal translocation Philadelphia chromosome was identified that generates a novel kinase that is always active, the retinoblastoma, pRb. The process normally controlled by this kinase is stuck in the 'on' position.

This leads to the proliferation of tumor cells Stehelin was one of the first researchers to understand the direct involvement of protein kinases in tumors, with the study of the oncogene v-SRC This tyrosine kinase with the phosphate group of Tyr has a key role in tumor cell proliferation, and has been studied extensively in Rous sarcoma virus RSV as the main cause of sarcoma in chickens 89 — Its carcinogenic action is due to a mutation of the carboxyl terminal of the molecule able to eliminate the tyrosine residue, which causes conformational changes and also an irregular unregulated autophosphorylation, leading to a signal of increased growth 93 , Aberrations of kinases have been reported in different types of cancer.

Phosphorylation plays a key role even in oral cancer. Endothelial growth factor receptor EGFR signaling. Ligand binding to the EGFR activates its intrinsic tyrosine kinase activity. Alteration of the phosphoproteome also affects gastrointestinal stromal tumors GISTs 98 , 99 , lung cancer 73 , , hematologic malignancies , , breast cancer , , pancreatic cancer , and prostate cancer , To date, more than 1, variations in the expression of protein kinases have been detected in human tumors — In tumors, mTOR Fig.

The Ras oncogene Fig. It begins with the binding of a ligand to a receptor tyrosine kinase RTK loca ted on the plasma membrane. This receptor is activated only if it dimerizes with another RTK. They then phosphorylate each other and become activated. The activated receptor binds to the SH2 domain of the adapter protein Grb2, which plays its role without being phosphorylated. The signaling pathways regulated by protein kinases contribute to the onset and progression of almost all types of cancer.

Consequently, research of the signaling pathways mediated by kinase and therefore the possibility of blocking them with targeted treatment could have major clinical-therapeutic utility especially since many of these proteins act as oncogenes 78 , , Considerable advances have led to the identification of inhibitors directed against activated tyrosine kinases in cancer, 17 of which are already used for the treatment of several cancers and more than molecules are being tested If overexpressed, HER2 is a protein tyrosine kinase which enhances the proliferation of cancer cells, and enhances the formation of blood vessels thereby increasing the invasiveness of breast cancer.

The simultaneous inhibition of these targets induces a reduction in tumor vascularization and triggers cancer cell apoptosis. It has been recommended as a drug in renal cell carcinoma and in GISTs , Furthermore, since sunitinib targets many different receptors, it leads to dermatologic toxic side effects such as hand-foot syndrome Temsirolimus leads to cell cycle arrest in the G1 phase, and also inhibits tumor angiogenesis by reducing synthesis of VEGF The success of therapies based on kinase inhibitors relies on different aspects: the clinical targeted kinase, the structure of the signaling network and the mechanisms of innate or acquired resistance.

First of all, both the patients and the therapeutic approach functions must be appropriately selected However, not all tumors respond to inhibitors of kinases and often patients with the same cancer respond differently to the same therapy. For this reason, patients should be further stratified using biomarkers and further studies are warranted to investigate the signaling pathways — In this respect, we know that changes in the signaling pathways, caused by several factors genetic and epigenetic mutations, alterations of the microenvironment , lead to the formation of oncogenes and, very often, there is a release of tumoral molecules that can be tracked and used as biomarkers.

The signaling networks of cancer cells can also develop innate or acquired resistance, since they are able to create the most common or rare oncogenic mutations different from tumor to tumor the so-called polygenic tumor biology There are two main types of resistance to a drug treatment based on kinase inhibitors.

Intrinsic or innate resistance on target occurs when the drug target protein has changed due to steric hindrance to inhibitor binding , altered active site topography , disruption of favorable inhibitor interactions , altered protein dynamics , increased oncogenicity , and alteration of ATP affinity In this way, this resistance is not inhibited by the drug and continues to perform its normal activity in the tumor cell.

The cancer cells are able in fact to exploit and reactivate the mechanism of signaling that the drug would inhibit In addition, during treatment acquired resistance can occur and the tumors can develop subclones which foster even relapse. New studies of the signaling network of tumors with particular attention to the mechanism of action of drug inhibitors of protein kinases are therefore needed. Phosphoproteomics has a critical relevance for many aspects of biology and has a significant role for understanding the molecular mechanisms, especially those that lead to the genesis and growth of tumors 77 — Signaling networks in which protein kinases operate are highly complex, but we believe that understanding the regulatory functions of kinases may be a valid means to identify more effective therapies against cancer , Many drug kinase inhibitors are already on the market , — but, often, their effectiveness is reduced due to the development of complex mechanisms of drug resistance However, great progress has been made in recent years thanks to the numerous techniques of proteomics.

Proteomics is the most important way by which to study the sites and behavior of phosphoprotein and phosphosite in tumor biology. The identification of biomarkers that aid in the selection of the most appropriate therapy for individual patients remains a major challenge National Center for Biotechnology Information , U. Int J Mol Med. Published online Jun Author information Article notes Copyright and License information Disclaimer. Received Jan 17; Accepted May This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

This article has been cited by other articles in PMC. Keywords: protein phosphorylation, kinase, phosphatase, phospho-signaling networks, cancer, drug target. Introduction Protein phosphorylation is one of the most common and important post-translational modifications PTMs 1 , 2. Open in a separate window. Figure 1. Protein kinases The protein kinases belong to the great family of kinases and are responsible for the mechanism of phosphorylation.

Table I Subfamilies of protein kinases. Protein kinase family Origin of the name Description Refs. They are important for expression of various genes because after activation, CAMKs phosphorylate several transcription factors.

Abnormalities in MAP kinase cascades are tightly linked to oncogenic transformation 23 GSK3, initially described as a key enzyme involved in glycogen metabolism, is now known to regulate a diverse array of functions. TKs are cell surface receptors RTKs and many of the others function close to the surface of the cell 19 TKL T yrosine k inase- l ike Tyrosine kinase-like kinases are serine-threonine protein kinases named so because of their close sequence similarity to tyrosine kinases.

Protein phosphatases Phosphatases have the opposite function of kinases. Activities and role of protein phosphorylation under physiological conditions Protein phosphorylation is one of the initial steps that is vital for the coordination of cellular and organic functions such as the regulation of metabolism, proliferation, apoptosis, subcellular trafficking, inflammation, and other important physiological processes.

Protein phosphorylation and cancer Phosphorylation is one of the most common PTMs involved in the regulation of multiple biological processes and overexpression of kinase.

Figure 2. Protein kinases as drug targets The signaling pathways regulated by protein kinases contribute to the onset and progression of almost all types of cancer. Conclusions Phosphoproteomics has a critical relevance for many aspects of biology and has a significant role for understanding the molecular mechanisms, especially those that lead to the genesis and growth of tumors 77 — References 1. Elucidating human phosphatase-substrate networks. Sci Signal.

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Mol Biosyst. Neph1, a component of the kidney slit diaphragm, is tyrosine-phosphorylated by the Src family tyrosine kinase and modulates intracellular signaling by binding to Grb2. Nuclear localization signal and phosphorylation of Serine specify intracellular localization of DRAK2.

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