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VOL. 73 (4), 901-925, 2007 ROLES OF PROTEIN PHOSPHATASE TYPE 1...

reflects the diversity and extension of this regulatory mechanism (1,
2). In contrast to initial views of signalling pathways as simple linear
arrangements of phosphorylation cascades that function in isolation,
it is now clear, that there are multiple signalling networks that
function in coordination. The level of phosphorylation of a protein
within a signalling pathway is thus a dynamic process that is
determined by the concerted action of protein kinases and
phosphatases (3).

Protein phosphorylation has also been linked to human diseases
and many protein kinases have been characterized (4). It has been
reported recently that protein kinases have become the second largest
drug targets for the pharmaceutical industry (5). In contrast, protein
phosphatases have lagged behind and only more recently have been
recognized as partners in the regulation of signalling responses. The
distinct but complementary function of these enzymes have found
their role in controlling the rate and duration of the cellular response
activated by protein kinases (6).

The physiological importance of protein phosphatases was
demonstrated initially when they were shown to be the targets of
many naturally occurring toxins and they could also function as
tumour suppressors. Later they were found to be the target of viral
proteins, including the viral oncoprotein E4orf4 and the middle-T
and small-T antigens (7, 8). More recently, large-scale loss-of-
function RNA interference (RNAi) screens have revealed that a
surprising number of phosphatases are promoters of cell survival
and cell death as well as having roles in the regulation of cell cycle
progression (8, 9).

CLASSIFICATION OF PROTEIN PHOSPHATASES

Protein phosphatases can be classified into three groups on the
basis of sequence, structure and catalytic mechanism (Figure 1A).
The first group comprises the classic Ser/Thr phosphatases: the large
phosphoprotein phosphatase family (PPP family) that includes PP1,
PP2A, PP2B, PP4, PP5, PP6 and PP7 and the protein phosphatase,
Mg2+ or Mn2+ dependent (PPM) family (PP2C). The protein Tyr
phosphatase (PTP) superfamily forms the second group, and the

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