Question

[4/30/9] DESCRIBE THE REGULATORY FUNCTION OF MITOGEN ACTIVATED KINASE PROTEINS (MAPKS).

[Typed please. (sometimes I can't understand the handwriting in some of the responses I get)]

Answer 1

Mitogen Activated Kinase Pathway

MAP kinase pathway is one of the most important signaling pathway in eukaryotes which is closely related to regulation of functions such as cell growth, proliferation,cell division (mitosis), differentiation and cell death. Over activation of this pathway can lead uncontrolled cell division resulting in a condition known as carcinoma or cancer. Hence its important to know the regulatory mechanism of MAPK.   

Pathway Summary   

1. Ligands or Signaling molecule : Binding of a signaling molecule is essential for initiation of any pathway. Specific molecules are required for initiation of each different pathways. As name suggest MPAK refers to an increase in mitosis or cell division so the ligands are mainly growth factors. Eg: EGF (epidermal growth factor), FGF( fibroblast growth factor), PGDF ( platelet derived growth factor) etc.
2. Receptor: These are located on the membrane of the cell to which the ligands bind. Receptors are ligand specific ie they bind only to particular type of signaling molecule and undergo confirmational  changes to carry the Cell Signaling forwad. In MPAK auto phosphorylation of the tyrosine residue of the receptor causing dimerization of the receptor Eg: EGFR (epidermal growth factor receptor)
3. Activation of the cascade: Series of activities are initiated inside the cell following the conformational change of the receptor molecule.

• GRB 2 molecule binds to the phosphorylated tyrosine in the receptor through its SH2 domain, which in turns activate the SOS protein.
• SOS protein binds to the GRB 2 molecule through SH3 domain.
• SOS replaces the GDP from the RAS domain into GTP activating the RAS. RAS is important for the initiation of cell division.
• RAS phosphorylate and activate the RAF called as MAP-KKK( MAP kinase kinase kinase).
• RAS inturn activate the MEK which is also called as MAP KK
• MEK activates the final activation product of this pathway   ERK or MAPK

Target activation

MAPK can act on different target in cytoplasms as well as nucleus.

Cytoplasam:

i) MAPK activates Activator Protein 1 (AP1) transcription factor from c-JUN and c-FOS. AP1 enters the nucleus and binds to the DNA.

ii) MAPK activate the ribosomal S6 kinase (RSK) latter activating the S6 . S6 enters the nucleus regulating the transcription factor CREB.

Nucleus

i) In the nucleus the MAPK directly activate the C myc transcription factor.

Regulation

i) S6 molecule down regulates the SOS molecule which is important for the initiation of the pathway.

ii) GAP inhibits the hydrolysis of RAS GDP into RAS GTP inhibiting the further progress of the cascade.

iii) de phosphorylation of the threonine and tyrosine by PP2A, PP2C

iv) MKPs molecules which dephosphorylate theorine and tyrosine eg:MKP 1, MKP 2

All these down regulate the cell division activated by the MAPK