18. Cell signaling II. Receptor tyrosine kinases. The Ras/MAPK, PI3K/Akt and PLC/CaMK pathways

receptor tyrosine kinase

They are a subgroup of cell surface receptors with intrinsic (own) enzymatic activity. Examples are: EGF receptor, PDGF receptor, insulin receptor. The receptor is activated in dimers or higher oligomers. The dimerization partners trans-phosphorylate each-other on tyrosine residues. Phosphotyrosine residues are recognized by SH2 or PTB domains of specific proteins forwarding the signal further into the cell. These can be adaptor proteins like Grb2 which activates the SOS guanine nucleotide exchange factor, or enzymes like phospholipase C, PI3K, or phosphotyrosine phosphatase which implements a negative feedback in the receptor’s signaling.

EGF receptor

It belongs to the receptor tyrosine kinase subgroup of cell surface receptors with intrinsic (own) enzymatic activity. Binding of epidermal growth factor (EGF) leads to receptor activation only when the receptor is in dimers or higher oligomers. The dimerization partners transphosphorylate each-other on tyrosine residues. Phosphotyrosine residues are recognized by specific proteins forwarding the signal further into the cell. Mutations leading to constant activation and/or over-expression of EGFR may cause tumors, so EGFR is a typical exmple of a proto-oncogene.

ras

A monomeric G protein, which takes part eg. in signaling by the EGF receptor as an intracellular switch. It is active in GTP bound form, and it hydrolizes GTP to GDP to become inactive. GAPs (GTPase activating proteins) enhance its GTP hydrolytic activity, while GEFs (guanine nucleotide exchange factor, eg. SOS) help the exchange of GDP for GTP, causing its activation. Its important effectors are kinases of the MAPKKK family which promote cell division. Hence ras is an important protooncogene.

MAPK pathway

The mitogen activated protein kinase (MAPK) pathway is one of the earliest recognised signaling route regulating cell division (but also other metabolic processes). Its central protein is the monomeric GTPase switch, Ras, which activates members of the MAPKKK family, which phosphorylate members of the MAPKK family, which activate the MAP kinases. MAPK family members phosphorylate further kinases and transcription factors regulating cell division, such as SRF (serum response factor) and c-Jun.

insulin receptor

A heterotetrameric cell surface receptor with intrinsic enzyme activity. It belongs to the subgroup of receptor tyrosine kinases. It is activated by autophosphorylation upon binding insulin. It also phosphorylates various intracellular proteins, including the insulin receptor substrate 1 (IRS1). It activates among others the PI3K-Akt and the Ras-MAPK signaling pathways, which make possible the uptake and storage of glucose into the cell, enhance the survival and protein synthesis of the cell, and promote mitosis.