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The serine/threonine kinase PAK4 prevents caspase activation and protects cells from apoptosis
1Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Abstract:
The serine/threonine kinase PAK4 was identified first as an effector molecule for the Rho GTPase Cdc42. PAK4 differs from other members of the PAK family both in sequence and function. Previously we have shown that an important function of this kinase is to mediate the induction of filopodia in response to activated Cdc42. Studies with a constitutively active PAK4 mutant have shown that it also has a role in promoting anchorage-independent growth, an important hallmark of oncogenic transformation. Here we show that another function of PAK4 is to protect cells against apoptotic cell death. Expression of wild-type or constitutively active PAK4 delays the onset of apoptosis in response to tumor necrosis factor alpha stimulation, UV irradiation, and serum starvation. Consistent with an antiapoptotic function, expression of PAK4 leads to an increase in phosphorylation of the proapoptotic protein Bad and an inhibition of caspase activation.
Insights
The serine/threonine kinase PAK4 protects cells from programmed cell death. This protein kinase, PAK4, also promotes anchorage-independent growth, a key cancer development factor.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The serine/threonine kinase PAK4 is an effector of the Rho GTPase Cdc42.
- PAK4 exhibits unique sequence and functional characteristics within the PAK kinase family.
- Previous research demonstrated PAK4's role in mediating Cdc42-induced filopodia formation.
Purpose of the Study:
- To investigate the role of PAK4 in cellular apoptosis.
- To determine if PAK4 influences cell survival under various apoptotic stimuli.
- To elucidate the molecular mechanisms underlying PAK4's antiapoptotic function.
Main Methods:
- Expression of wild-type and constitutively active PAK4 in cells.
- Induction of apoptosis using tumor necrosis factor alpha, UV irradiation, and serum starvation.
- Analysis of apoptosis markers, including Bad phosphorylation and caspase activation.
Main Results:
- Expression of PAK4, both wild-type and constitutively active forms, delays apoptosis.
- PAK4 confers resistance to apoptosis induced by TNF-alpha, UV irradiation, and serum starvation.
- PAK4 enhances the phosphorylation of the proapoptotic protein Bad.
- PAK4 inhibits the activation of caspases, key executioners of apoptosis.
Conclusions:
- PAK4 possesses a significant antiapoptotic function, protecting cells from death.
- PAK4's antiapoptotic activity is mediated through the modulation of Bad phosphorylation and caspase activation.
- PAK4's dual role in promoting anchorage-independent growth and inhibiting apoptosis suggests its involvement in oncogenic transformation.