Role of Tyrosine Kinase Receptors in Growth Factor Mediated Signal Transduction, with Specific Reference to MAPK/Rasand p13k-Akt Containing Pathways in Oncogenesis: A Qualitative Database Review

Receptor Tyrosine kinases (RTKs) play a crucial role in the signal transduction pathways at cellular levels. RTK plays a vital role in cellular communica-tion and transmission of signals to the adjacent cells and regulates different functions of the cell, such as cellular growth, differentiation, metabolism and motility. RTK s triggers growth factor receptors such as epidermal growth factor, insulin growth factor-1 receptor, platelet derived growth factor receptor, and fibro blast growth factor receptor and vascular endothelial growth factor receptor, thereby initiating and regulating cell growth and proliferation. MAPK/RAS and PI3/AKT pathways are the major pathways of RTK’s function. Dysregulation of these RTK’s and pathways often leads to many diseases such as Noonan Syndrome, Logius Syndrome, CFC syndrome and different types of cancer. Point mutation and over expression of receptors and mutations in Ras leads to 30% of human cancers. Also over expression of different growth factor receptors by RTK too lead to several types of cancers as Glioblastoma, Thyroid cancer, Colon cancer and Non-small cell lung cancer. PTEN mutation in PI3/AKT pathway often leads to carcinoma relative to Thyroid, Skin, Large intestine, eye and Bone. Therefore, these RTK’s often used as targets for cancer therapies. The medical sector uses various


Introduction
Receptor tyrosine kinases (RTKs) belong to the enzyme coupled receptor family.
These are vital components of Growth factor mediated signal transduction pathways [1]. These RTKs are transmembrane proteins usually monomers that hold 90 human genomic kinases. Out of them, 58 is receptor types belong to 20 sub families. The rest of the 32 are non-receptor types of 10 subfamilies [2].
During homeostasis and embryonic development, RTKs are mostly active.
This also regulates cell growth, division, cell survival and cellular metabolism [3]. Domains and ligands of RTKs are illustrated in Table 1 respectively.

PI3-AKT Pathway
The binding of one of the ligand EGF to the ligand binding domain of RTK leads to the activation of PI3-AKT pathway. This binding also auto phosphorylates the RTK which activates PI3 kinase. Activated PI3 kinase adhere and phosphorylates PIP2 which is a standard constituent of the cell membrane to PIP3. This PIP3 thereby activates serine, threonine kinases (AKT) pathway which promotes cellular growth, proliferation, glucose metabolism and inactivates apoptosis. This pathway is controlled by a regulator called Protein tyrosine phosphate (PTEN) which can change the activated PIP3 to PIP2 [8].

Role of the Pathways to Promote Cell Survival and Proliferation Which if Unchecked Can Be Pathogenic
In normal cells, MAPK/RAS and PI3/AKT pathways lead to cell growth and proliferation via initiating transcription factors (AP-2, Elk, CREB) and also protein synthesis. Whereas in a cell cycle Go and G1 phases play a vital role. However, these phases depend on ERK 1/2 signal transduction [9].

MAPK/RAS Pathogenesis
Mutation of this pathway leads to so many genetic disorders as well. It has some profound effects on CFC, CS, NF1, NS and NSML [13].  Also, over expression of receptors and mutations in Ras leads to 30% of human cancers [16]. Ras protein activation can constitutively occur due to single point mutations in Ras where GTPase activities become impaired leading to proliferation and carcinoma [17]. Table 2 below indicates the different varieties of carcinoma due to RTK mutation.

PI3 AKT Pathogenesis
PI3/AKT pathway is negatively controlled by PTEN. Deletion of PTEN and mutation in PI3K1 could be seen in prostate cancer. Through p110, the major sub unit of PI3K1 leads to hyper continuous activation of this pathway which gradually leads to carcinoma [26]. This mutation of PTEN is observed in various types of cancers as shown in Table 3 below.
Clinical trials have elucidated, ovarian cancer and breast cancer mutations in PI3KCA, PI3K, PTEN, p95 and AKT mutation, overexpression of receptors leads to permanent proliferation of cancerous cells [28].

Tyrosine Kinases as the Target for Cancer Therapy
The most common type of anti-cancer therapy is conventional chemotherapy   Table 4 and Table 5 [30].
Monoclonal antibodies are commonly used, which are highly specific that binds to the extracellular domain of RTK and secreted protein. These prevent ligand-receptor interaction, dimerization of receptors and activation of pathways.
At times, it leads to shedding off the extracellular portion of receptors eventually Table 4. Types of small molecule tyrosine kinase inhibitors [30].

Ongoing Research on Tyrosine Kinase and Cancer Therapy
Moreover, literature showcases drug resistance as the major challenge for therapy. For example, "Imatinib" is a small molecule tyrosine kinase inhibitor used to treat CML. This binds to the ATP binding side of BCR-ABL protein and inhibits the signal for CML Due to drug resistance and point mutation, BCR-ABL changes its confirmation where "Imatinib" cannot be used longer [35].
If the drug inhibits one pathway, a corresponding and independent pathway can take over carcinogenesis. For example, in drug resistance MAPK/RAS and PI3/AKT pathway alters Hippo pathway responsible for degradation [36]. Therefore, recently scientists have been working on a combination regimen of drug therapy based on different signaling pathways of receptor tyrosine kinase [37].

Conclusion
The high prevalence of cancer worldwide opens up gates for therapies and new discoveries. Such that Receptor tyrosine kinases will be a potential target to transit treatment patterns from classical chemotherapy to target therapy. Although scientific research found inhibitors, monoclonal antibodies and target components for these RTK signaling pathways in cancer therapy, mutations by the cancer cells and their resistance to these inhibitors are still a challenge for cancer therapy. Moreover, apart from the classical treatment and prevention, using the receptors like RTK is still a magic bullet in the treatment and prevention of cancer progression.