Under normal, non-stimulated conditions, MARCKS binds to and sequesters the lipid messenger, PIP2 (PHOSPHATIDYLINOSITOL 4,5 BIPHOSPHATE) in lipid rafts in the plasma membrane. This keeps PIP2 from being activated.
When MARCKS is phosphorylated by PKC, PIP2 – MARCKS binding is disrupted, and PIP2 is released from its sequestration sites in the membrane.
Once released, PIP2 then can act to stimulate processes required for cell migration. For example PIP2:
- Promotes assembly of ACTIN filaments
- Regulates expression of ACTIN-binding proteins (E.G. TALIN)
- Promotes polarization of vesicle trafficking resulting in formation of the leading edge
- Regulates INTEGRIN expression
- Regulates E-CADHERIN expression and focal adhesion plaques
These events act to promote cell migration.
Cancer cells have high expression of PHOSPHORYLATED MARCKS; thus, there is a high level of pro-migration events modulated by PIP2.
bioMARCK peptides decrease PHOSPHORYLATION of MARCKS, keeping it bound to PIP2 and blocking the above events.
Of course, it is much more complicated: PIP2 is converted to PIP3 via PI3 KINASE, and PIP3 can activate the AKT pathway, which regulates many cell cycle events; the conversion of PIP2 to PIP3 is inhibited by the tumor suppressor PTEN; more aggressive cancer cells have lower levels of PTEN.