Question

Diagram the HER2 signaling pathway from ligand binding to the expression of cyclin. What effects does this have on the cell? What are the different proteins along this pathway and describe their functions.

Answer 1

Ans : HER2 or ERBB2 (Erythroblastic Oncogene) is a proto oncogene located in the q arm of chromosome 17. Over expression of HER2 gene has been identified as the cause for breast cancer. The protein coded by it is a receptor tyrosine kinase, a transmembrane protein in the plasma membrane. It characteristically dimerizes with other other members of receptor trosine kinase family like Epidermal growth factor receptor (Erb-3). This leads to autophosphorylation if tyrposine residues in the cytoplasmic domain of the receptors which in turn activates a variety of downstream signalling pathways that result in cell proliferation and tumor formation.

  

The following proteins are involved in HER2 signalling pathway :

• PI3K - Phosphoinositide-3-kinase, involved in P13K/AKT/mTOR pathway in regulation of cell cycle. It activates AKT
• AKT - Protein kinase B, phosphorylates several pro-apoptotic proteins(eg : MDM2) involved in cell proliferation, inhibiting cell cycle arrest in G1 and G2 phases
• Phospholipase C (PLC) - cleaves phospholipids at the phosphate group. It is involved in signal transduction pathways that result in proliferation. One example is activation of PKC.
• PKC (Protein Kinase C) - phophorylates proteins in a phosphorylation cascade. Activated protiens that promote transcriptional activation of cell proliferation.
• GSK3 - Glygogen synthase kinase 3, a serine/ threonine protein kinase that selectively phosphorylates several substrates involved in regulation of apoptosis and glycogen metabolism
• MDM2 - Murine double minute 2 homolog , inhibits transcriptional activation of TP53 (Tumor supressor gene)
• mTOR - mammalian target of rampamycin, involved in regulation of metabolic homeostasis in the cell. It downregulates energy consuming metabolic activities in the cell and promotes biogenesis pathways that leads to cell multiplication.
• GRB2 - Growth factor receptor bound protein, involved in transduction pathways of cell proliferation. It binds with ERB2 and activates RAS protein
• SOS - Son of sevenless family, codes for Guanine nucleotide exchange factor that act on RAS protein and activate it.
• RAS - Small GTPase family, involved in regulation of cell proliferation, apoptosis and cell differentiation. It activates a signal transduction pathway in the cytoplasm that leads to cell proliferation
• RAF - Serine/threonine protein kinase proto-oncogene, activated by RAS protein, targets and activates MEK proteins by phosphorylation
• MEK - Serin/tyrosine/threonine kinase from mitogen activated protein kinase family, stimulates activation of MAPK proteins
• MAPK - Mitogen activated protein kinase, activates MKK protein involved signal pathway that leads to activation of transcription and cell proliferation
• Cyclin - proteins that promote progression of cell cycle by associating with CDK(Cyclin-dependent kinse) enzymes. It is activated by the signal transduction pathway initiated by dimerization of HER2 with other HER proteins
• CDK4 - Cyclin dependent kinase 4, from serine/threonine protein kinase family. Activated by cyclin D, promotes transition of G1 phase to S phase of cell cycle, inhibited by P16 protein.