[Frontiers in Bioscience 3, d1262-1273, December 15, 1998]

	[Frontiers in Bioscience 3, d1262-1273, December 15, 1998] Reprints PubMed CAVEAT LECTOR
	ROLE OF PP2A IN INTRACELLULAR SIGNAL TRANSDUCTION PATHWAYS Axel H. Schönthal Department of Molecular Microbiology and Immunology, K. Norris Jr. Comprehensive Cancer Center, University of Southern California, 2011 Zonal Ave., HMR-405, Los Angeles, CA 90033 Received 8/25/98 Accepted 12/2/98 7. INTERACTION OF PP2A WITH OTHER REGULATORY PROTEINS The involvement of PP2A in intracellular signal transduction pathways can be inferred most directly from experiments that establish the interaction of this enzyme with other cellular regulatory components. For example, most recently it was found that the trimeric PP2A holoenzyme can form a stable complex with Ca²⁺- calmodulin-dependent kinase IV (CaMKIV) (138). In this interaction, PP2A serves to ensure the transient nature of CaMKIV activation: after the kinase has phosphorylated its substrates, CaMKIV activity is down-regulated by PP2A. Thus, this association of a phosphatase with a kinase, where PP2A functions as the negative regulator of CaMKIV, allows tight control of the corresponding signal transduction pathway. In other studies, PP2A has been shown to interact with casein kinase 2alpha (CK2alpha) in mitogen starved cells (139). CK2alpha was found to negatively regulate the activity of the mitogen-activated protein kinase (MAPK) pathway. This inhibition appears to be mediated through the phosphorylation/activation of PP2A by CK2alpha, and the subsequent dephosphorylation/deactivation of MAPK kinase (MEK) by PP2A (78, 139). Because the MAPK pathway is one of the major growth regulatory pathways, these findings provide yet another example of the apparently crucial role of PP2A in cellular growth control. Several other cellular signaling proteins have been identified that interact with PP2A (140-142). Notably HOX11, a homeo box gene product which is able to transform cells, associates with the catalytic subunit of PP2A (143). This interaction is thought to affect alterations of cell cycle progression induced by HOX11. In other studies, the translation termination factor eRF1 (eukaryotic release factor 1) has been found complexed with PP2A, which may serve to bring the phosphatase into contact with putative targets among the components of the translational apparatus (144). In addition, the recruitment of PP2A to signal transduction pathways and other regulatory events may be regulated through its B-type subunits, which may add yet another layer of control and specificity. In this regard, it has been found that the B’alpha and the B’beta subunits of PP2A form complexes with cyclin G, a protein whose expression is regulated by the tumor suppressor p53 (145). Because induction of p53 protein appears to be required for this complex formation, the existence of specific cross-talk between PP2A and p53-mediated pathways has been suggested (145).

[Frontiers in Bioscience 3, d1262-1273, December 15, 1998]
Reprints
PubMed
CAVEAT LECTOR

ROLE OF PP2A IN INTRACELLULAR SIGNAL TRANSDUCTION PATHWAYS

Axel H. Schönthal

Department of Molecular Microbiology and Immunology, K. Norris Jr. Comprehensive Cancer Center, University of Southern California, 2011 Zonal Ave., HMR-405, Los Angeles, CA 90033

Received 8/25/98 Accepted 12/2/98

7. INTERACTION OF PP2A WITH OTHER REGULATORY PROTEINS

The involvement of PP2A in intracellular signal transduction pathways can be inferred most directly from experiments that establish the interaction of this enzyme with other cellular regulatory components. For example, most recently it was found that the trimeric PP2A holoenzyme can form a stable complex with Ca²⁺- calmodulin-dependent kinase IV (CaMKIV) (138). In this interaction, PP2A serves to ensure the transient nature of CaMKIV activation: after the kinase has phosphorylated its substrates, CaMKIV activity is down-regulated by PP2A. Thus, this association of a phosphatase with a kinase, where PP2A functions as the negative regulator of CaMKIV, allows tight control of the corresponding signal transduction pathway.

In other studies, PP2A has been shown to interact with casein kinase 2alpha (CK2alpha) in mitogen starved cells (139). CK2alpha was found to negatively regulate the activity of the mitogen-activated protein kinase (MAPK) pathway. This inhibition appears to be mediated through the phosphorylation/activation of PP2A by CK2alpha, and the subsequent dephosphorylation/deactivation of MAPK kinase (MEK) by PP2A (78, 139). Because the MAPK pathway is one of the major growth regulatory pathways, these findings provide yet another example of the apparently crucial role of PP2A in cellular growth control.

Several other cellular signaling proteins have been identified that interact with PP2A (140-142). Notably HOX11, a homeo box gene product which is able to transform cells, associates with the catalytic subunit of PP2A (143). This interaction is thought to affect alterations of cell cycle progression induced by HOX11. In other studies, the translation termination factor eRF1 (eukaryotic release factor 1) has been found complexed with PP2A, which may serve to bring the phosphatase into contact with putative targets among the components of the translational apparatus (144).

In addition, the recruitment of PP2A to signal transduction pathways and other regulatory events may be regulated through its B-type subunits, which may add yet another layer of control and specificity. In this regard, it has been found that the B’alpha and the B’beta subunits of PP2A form complexes with cyclin G, a protein whose expression is regulated by the tumor suppressor p53 (145). Because induction of p53 protein appears to be required for this complex formation, the existence of specific cross-talk between PP2A and p53-mediated pathways has been suggested (145).