Question

How are Cdks activated? Be sure to include in your answer the roles of:
a) Cyclin
b) CAK

Answer 1

Cyclin dependent kinases (Cdks) play a key role in cell's progression through different phases of cell cycle. Activity of Cdks are regulated by various ways like

Binding with cyclins

Phosphorylation by Cdk activating kinase

a Activation of Cdks by binding of cyclins (first step- partial activation)

Concentration of CDKs remains constant inside the cell, all the time (irrespective of phase of cell cycle) Although, CDKs alone can not function. They need assistance from binding of different cyclins to become active. Concentration of cyclins keep varying during the cell cycle, CDKs can phosphorylate the target proteins only when they are bound by a particular cyclin.

Ex-Cdk 4 and 6 bind with cyclin D and help in progression from G1 to S phase by phosphorylating many target proteins (Rb, retinoblastoma)

b.Activation of Cdks by Cdk activating kinases (CAK) - Second step- full activation

After binding with cyclins, Cdks becone active but activation of full kinase activity, recquire another phosphorylation on threonine residue (close to active site ) by a different class of kinases (Cdk activating kinases ). In mammals, this phosphorylation of Cdks happens only after binding of cyclins.(unlike yeast cells) Concentration of CAK always remains high in the cell, but it can only phosphorylate Cdks after Cdk is bound by cyclins

Free cdk (inactive)- cdk+cyclin (partially active)- Cyclin+cdk+phosphorylation on threonine residue by CAK (highly active)

Cdks and CAK both are constitutively present in the cell. Hence, binding of cyclin is rate limiting.

Apart from above mentioned main regulatory steps, activity of Cdks are additionally regulated by inhibitary phosphorylation by Wee1 type of serine threonine kinases. These phosphorylations can be removed by phosphateses like cdc25 to reactivate the Cdks