Receptor Signaling Pathways Essay - 1650 Words

Receptor Signaling Pathways and its Association with to Apoptotic Pathways (Research Paper Sample) Content: Receptor Signaling Pathways and its Association with to Apoptotic PathwaysName:Institution:AbstractHER2 positive breast cancers is quite common in women. The human epidermal growth factor receptor 2 (HER2) encourage the proliferation of cancer cells (Moynihan, 2015). HER2 is one of a collection of proteins that belongs to the human epidermal growth factor receptor family of proteins. These proteins hinder tumor cell death due to its influence on oncogenic feedback processes which control specific pathways associated with programmed cell death (Green, 2011). Apoptotic mitochondrial pathways facilitate the death of tumor cells via HER2 inhabitants. This paper will cover the connections between oncogenic signaling system and some particular mechanisms of the mitochondrial apoptotic pathway. Knowledge on signaling pathways is vital in discovery and development of breast cancer drugs. I also give an insight into appropriate intervention and control drug resistant cancers which are determined by how they respond to regulatory interactions (Fink Chipuk, 2013; Lu, Zi, Zhao, Mascarenhas Pollak, 2001).Key words: HER2 human epidermal growth factor receptor 2, breast cancer, signaling pathways.Introduction The human epidermal growth factor receptor 2 (HER2) play a critical role in the generation breast cancer. This protein tends to inhibit apoptosis of cancerous cells. HER2 and receptor tyrosine protein kinase can be used interchangeably. This protein do interacts with a various kinds of signaling molecules. They demonstrate both ligand dependent as well as ligand independent activities. The HER2 gene is a well known proto oncogene which is located in the long arm of the human chromosome 17 (17q12). HER2-positve tumors are obvious in about 25% of all early breast cancer patients. Scientist and governments have dedicated their energy and resources on research on the HER2 signaling research. Scientists have not yet reached an evidence-based conclusio n (Fink Chipuk, 2013). Unregulated proliferation and maturity of the cells is initiated by the link between HER2-activated signaling pathways and its supporting systems in the cancerous cells. This paper will concern itself with the relationship between HER2 signaling-kinases and mitochondrial pathway of apoptosis. In brief, it will focus specifically on HER2 - signaling networks, apoptotic mechanisms and the connections between them which result in HER2 associated breast cancer, as well as its response to treatment (Fink Chipuk, 2013).HER2 Related Treatment Methods and Resistance Before the invention of treatment interventions which targets HER2, breast cancer patients used to experience an elevated rate of mortality. In addition, breast cancer recurrence was severely higher. Currently, numerous HER2 inhibitors have been generated, however only two drugs have been authorized for public use. Trastuzumab is indicated during early stages HER2 associated breast cancers. Trastuzumab is a monoclonal antibody drug which functions by binding the HER2 receptor. This hinders receptor function and hence generates and apoptotic signal (Fink Chipuk, 2013 Karam, 2009). Later stages of HER2 associated breast cancers most often resist the action of trastuzumab. Majority of tumors recur within a time span of 12months after treatment. HER2 associated breast cancers most often do not respond positively to trastuzumab treatment because of the initiation of PK13/AKT pathway. Another root of trastuzumab resistance is the buildup of truncated type of HER2, i.e. p95-HER2. Other kinds of tyrosine kinase receptors e.g. Met and IGF-1R, when over expressed give rise to trastuzumab resistance. Over expression of MUC4 masks the HER2 thus reducing its access as well as a reduction of trastuzumab binding (Green, 2011). Lapatinib is another drug which has been approved for the treatment of HER2 associated breast cancers. This drug has dual HER2/ Epidermal Growth Factor Receptor, (EGFR ) capacity. It is prescribed for the treatment of advanced HER2 associated breast cancers. Lapatinib have been found to be a dual HER2/EGFR inhibitor while in vitro but it appears to hinder HER2 in vivo. Lapatinib lowers the activity of HER2 thus subsequently lower the signaling mechanisms via several pathways. These pathways include RAF/MEK/ERK and P13K/AKT/mTOR pathways as well as apoptotic pathways (Green, 2011). Mechanism of resistance to Lapatinib has not been well described yet. There are theories whichattempts to explain this phenomenum, for instance the Lapatinib - mediated FOXO3 induction which increase the Estrogen Receptor (ER) activity thereby teaming up with HER2 to sustain the lives of cancerous cells. ER activity gives way to the induction of AXL. Over expression for the synthesis of receptor tyrosine kinase AXL may possibly be the cause of resistance. Another theory which attempts to explain this concept is the associated with Integrin complexes which causes the acti vatation of SRC as well as FAK activity. Other theories rely on enhanced signaling by the mTOR in a P13K independent mechanism (Karam, 2009). Recent studies by two teams involved the use of P13Kand AKT inhibitors in order to describe the alterations of receptors tyrosine kinase by the utilization of antibody arrays. Inhibition of P13K elevates the levels of phosphorylated IGF-1Rs, EGFRs, Insulin Receptors (IRs), HER3 and HER4, FGFR1, 3 and4, EPHA1, TIE2, TRKA, FLT3, MER, and MST1R. Removal of IR and IGF1R sensitizes the cells towards P13K inhibition. Other explanation was that Lapatinib initiates the expression of HER3 protein which inhibits cells from undergoing apoptosis (Reed Green, 2011 Fink Chipuk, 2013). More deductions from research were derived from microarray analysis results by utilization of BT474 cell lines. The data analysis showed that a number of receptor tyrosine kinases are usually transcriptionally controlled within a time span of 24 hrs after the intake of lapa tinib. These involve HER3 and HER4, IR, IGF-1R, and MER. Receptors which are up-regulated involves EPOR, LEPR, PTGER4, and NPY1R. Others examples include JAK1 and PIK3CA (Fink Chipuk, 2013). It is safe to conclude that FOXO-mediated transcription is vital for the response of the cancer cells after being exposured to medication. Other study found out that the levels of nuclear FOXO3a were elevated in BT474T cell line when they were exposured to Lapatinib treatment for 4 hours, consequently demonstrated that transcription factor might be responsible for induction of some of the target genes at the early stages of development of breast cancer. FOXO associated factors are believed to have capability of initiating the activities of apoptotic determinants e.g. BIM and KLF6. They also function in the induction of genes while play a critical role in cell survival (Jolesz Hynynen, 2007; Yarden, Sliwkowski, 2001).Her2 Signaling Pathways Epidermal Growth Factor Receptors (EGFRs) are made up four receptors, which are; EGFR, HER2, HER3 and HER4. All of them have a membrane- bound ligand - binding domain, trans-cellular domain, and trans-membrane domain. Heterodemirization of HER2 and 3 plays a vital role in the multiplication of HER2-positive breast cancer cells. A number of adapter proteins do bind on the HER2 and HER3 receptors after they have been tyrosine-phosphorylated receptor after tyrosine-phosphorylated. These proteins are subsequently phosphorylated on binding. These adapter proteins hence turn on the multiple signal transduction pathways. The major pathways are the RAF/MEK/ERK, (ERK cascade) and P13K/AKT/mTOR pathways (Genetech, 2015). INCLUDEPICTURE "/images/biological-pathways/her-main.jpg" \* MERGEFORMATINET 
 ERK cascade is build up by the incorporation of HER2, GRB2, as well as the SOS. SOS is a guanine exchange factor for RAS and activates it. RAS subsequently delivers RAF into the membrane whereby it is both phosphorylated and activated. Specific is oforms which are active in HER2 breast cancer have positively identified yet. ERK functions comprise scaffolding proteins which are active in this pathway. However, little is known about their role in the control of breast cancer cell signaling. ERK is involved in the phosphorylation and activation of RSK kinases which have significance in the survival of various kinds of breast cancers. RSK activity is initiated via the stimulation of HER2 positive breast cancer cells with a substance known as heregulin. A comprehensible elucidation of the precise means of this process is not clear (Genetech, 2015). P13K is incorporated into active growth-factors receptors in order to stimulate the AKT pathway. After P13K recruitment, its isoforms phosphorylates the membrane phospholipids at the third position that produces PIP3. AKT is thereby phosphorylated by PDK1 and TORC2 on the residues of T308 as well as S473. AKT pathway is regulated in a negative manner the by PTEN dephosphorylation of the PIP3. In the pathway several substrates are phosphorylated. These substrates are responsible for the propagation and endurance of HER2-positive breast cancer cells. Trastuzumab acts by blocking FOXOI inactivation by the AKT signaling which is important for effectiveness of this drug. Studies are being done on HER2 signaling pathways, which are targeted at expansion of knowledge for better understanding of breast cancer (Genetech, 2015; Yarden, Sliwkowski, 2001). Apoptotic Pathways Apoptosis is also referred to as programmed cell death. It involves a number of processes nuclear condensation as well as cleavage of cellular proteins. The induction processes which give rise to apoptosis comprise the extrinsic pathway as well as the mitochondrial pathway. Extrinsic pathway is specifically mediated by death receptors. More will be discu...