are called protein kinase C. To date, the sole
representatives of the third class are two protein
kinases from the ciliate Paramecium tetraurelia
and these are stimulated by Ca2+ ions independently of calmodulin or lipids [92]. Calmodulin is
a 17-kDa protein with four Ca z + -binding sites. It is
ubiquitous in the eukaryotes and extremely conserved in evolution; it belongs to the same family
as troponin C. The phosphorylase-b kinase is a
complex of 1.3 MDa, composed of 16 polypeptides according to the formula (a,~,y,o)4' The regulatory subunits a (118-145 kDa) and ~ (108128 kDA) can be phosphorylated at several positions by various protein kinases; in this way the
enzyme becomes activated. The catalytic ysubunit (44.7 kDa) is homologous to the catalytic
subunit of other protein kinases; the o-subunit is
identical to calmodulin. In vitro, the enzyme
phosphorylates other proteins in addition to
phosphorylase-b. A multi-functional protein
kinase, activated by Ca z + -calmodulin, is apparently commonly found. This phosphorylates a
range of very different substrates and thus participates as a regulator in many processes: glycogen
synthase and tyrosine hydroxylase (metabolism),
phospholamban (relaxation of heart muscle),
MAP-2 (dissociation of microtubules) and synapsin (release of transmitter at the synapse) [244].
Ca z + -calmodulin also indirectly affects the phosphorylation and dephosphorylation of proteins by
activation of adenylate and guanylate cyclase and
of protein phosphatase 2B.
The enzymes known as protein kinase C
require Ca z + and the phospholipid phosphatidylserine (PS) for their activity, and are stimulated
by DAG. They were first discovered in 1979,
although they are found in some mammalian tissues at levels far greater than other protein kinases. They playa central role in a system of signal
transduction through the cell membrane that acts
upon the membrane lipid phosphatidylinositol4,5-biphosphate (PIPz). There are various hormones, neurotransmitters and other extracellular
signals which cause the hydrolysis of PIPz to
inositol-l,4,5-trisphosphate (IP3) and DAG. The
IP3 releases Ca z + from intracellular stores and
thus influences many cellular processes through
the activation of particular protein kinases, protein phosphatases and proteases; this is caused by
the increase in the intracellular calcium concentration. The protein kinase C stimulated by Ca z +
and DAG actually consists of a whole family of
multiple enzymes; to date, seven enzymes of this
type, encoded by different genes, have been isolated from rat brain [140]. An inhibitor of protein
3.1.2 Phosphorylation and Dephosphorylation
75
kinase C has been isolated from bovine brain, and
is a zinc-binding polypeptide of 125 amino acids
without homology to any known protein [207].
Caz+-PS-DAG-dependent protein kinases are
apparently ubiquitous, having been detected in
lower vertebrates, echinoderms, annelids, crustaceans and insects, as well as in mammals
[217, 249]. Several protein kinase C genes known
in Drosophila show specific similarities to particular mammalian genes; this multi-gene family
is therefore apparently very old [242]. A protein
kinase C is also responsible for the phosphorylation of nuclear proteins and increased DNA synthesis that is induced by the aggregation factor
(AF) in the sponge Geodia gigas [115, 231]. There
are many protein kinases that are not stimulated
by either cAMP, cGMP or Ca z +. To these belong,
for example, the casein kinases I and II that are
widespread in both animals and higher plants.
Type I from mammalian kidney, spleen and liver
is a monomer of 37 kDa; Type II, which is found
in mammalian spleen and testis and also occurs in
Drosophila and Caenorhabditis, is a tetramer
az~z, the a-chain of which is homologous to the
catalytic chains of other protein kinases. In
bovine testis there are also tetramers of a'~z,
where the a I chain is encoded by its own gene
[63, 114, 160]. Other protein kinases that are not
regulated by secondary messengers include the
haem-controlled repressor (HCR) involved in
globin synthesis (p. 81); the pyruvate dehydrogenase kinase (p. 689) and the closely related kinase
for the dehydrogenase complex of the branched
keto-acids ketoleucine, keto isoleucine and ketovaline; the rhodopsin kinase (p. 736); the glycogen synthase kinase (p. 488); the kinase for the
ribosomal protein S 6 (p. 50); and the myosin HC
kinase from Acanthamoeba (p. 339) [63].
It appears that just a few protein phosphatases
suffice for the complicated regulation system of
protein phosphorylation and dephosphorylation
in the tissues of mammals. Four types of protein
serine/threonine phosphatases are known, of
which 1, 2A and 2B show significant mutual
homology, whereas 2 C belongs to another family.
The third family of protein phosphatases is that of
the protein tyrosine phosphatases [31]. The four
protein serine/threonine phosphatases may be
divided into two classes according to their catalytic and regulatory properties. Protein phosphatase 1 is specific for the ~-subunit in the reaction
with phosphorylase-b kinase and is inhibited by
two specific protein inhibitors 1 and 2. The three
enzymes belonging to the second class (2A, 2 B
and 2 C) are all specific for the phosphorylase-b
representatives of the third class are two protein
kinases from the ciliate Paramecium tetraurelia
and these are stimulated by Ca2+ ions independently of calmodulin or lipids [92]. Calmodulin is
a 17-kDa protein with four Ca z + -binding sites. It is
ubiquitous in the eukaryotes and extremely conserved in evolution; it belongs to the same family
as troponin C. The phosphorylase-b kinase is a
complex of 1.3 MDa, composed of 16 polypeptides according to the formula (a,~,y,o)4' The regulatory subunits a (118-145 kDa) and ~ (108128 kDA) can be phosphorylated at several positions by various protein kinases; in this way the
enzyme becomes activated. The catalytic ysubunit (44.7 kDa) is homologous to the catalytic
subunit of other protein kinases; the o-subunit is
identical to calmodulin. In vitro, the enzyme
phosphorylates other proteins in addition to
phosphorylase-b. A multi-functional protein
kinase, activated by Ca z + -calmodulin, is apparently commonly found. This phosphorylates a
range of very different substrates and thus participates as a regulator in many processes: glycogen
synthase and tyrosine hydroxylase (metabolism),
phospholamban (relaxation of heart muscle),
MAP-2 (dissociation of microtubules) and synapsin (release of transmitter at the synapse) [244].
Ca z + -calmodulin also indirectly affects the phosphorylation and dephosphorylation of proteins by
activation of adenylate and guanylate cyclase and
of protein phosphatase 2B.
The enzymes known as protein kinase C
require Ca z + and the phospholipid phosphatidylserine (PS) for their activity, and are stimulated
by DAG. They were first discovered in 1979,
although they are found in some mammalian tissues at levels far greater than other protein kinases. They playa central role in a system of signal
transduction through the cell membrane that acts
upon the membrane lipid phosphatidylinositol4,5-biphosphate (PIPz). There are various hormones, neurotransmitters and other extracellular
signals which cause the hydrolysis of PIPz to
inositol-l,4,5-trisphosphate (IP3) and DAG. The
IP3 releases Ca z + from intracellular stores and
thus influences many cellular processes through
the activation of particular protein kinases, protein phosphatases and proteases; this is caused by
the increase in the intracellular calcium concentration. The protein kinase C stimulated by Ca z +
and DAG actually consists of a whole family of
multiple enzymes; to date, seven enzymes of this
type, encoded by different genes, have been isolated from rat brain [140]. An inhibitor of protein
3.1.2 Phosphorylation and Dephosphorylation
75
kinase C has been isolated from bovine brain, and
is a zinc-binding polypeptide of 125 amino acids
without homology to any known protein [207].
Caz+-PS-DAG-dependent protein kinases are
apparently ubiquitous, having been detected in
lower vertebrates, echinoderms, annelids, crustaceans and insects, as well as in mammals
[217, 249]. Several protein kinase C genes known
in Drosophila show specific similarities to particular mammalian genes; this multi-gene family
is therefore apparently very old [242]. A protein
kinase C is also responsible for the phosphorylation of nuclear proteins and increased DNA synthesis that is induced by the aggregation factor
(AF) in the sponge Geodia gigas [115, 231]. There
are many protein kinases that are not stimulated
by either cAMP, cGMP or Ca z +. To these belong,
for example, the casein kinases I and II that are
widespread in both animals and higher plants.
Type I from mammalian kidney, spleen and liver
is a monomer of 37 kDa; Type II, which is found
in mammalian spleen and testis and also occurs in
Drosophila and Caenorhabditis, is a tetramer
az~z, the a-chain of which is homologous to the
catalytic chains of other protein kinases. In
bovine testis there are also tetramers of a'~z,
where the a I chain is encoded by its own gene
[63, 114, 160]. Other protein kinases that are not
regulated by secondary messengers include the
haem-controlled repressor (HCR) involved in
globin synthesis (p. 81); the pyruvate dehydrogenase kinase (p. 689) and the closely related kinase
for the dehydrogenase complex of the branched
keto-acids ketoleucine, keto isoleucine and ketovaline; the rhodopsin kinase (p. 736); the glycogen synthase kinase (p. 488); the kinase for the
ribosomal protein S 6 (p. 50); and the myosin HC
kinase from Acanthamoeba (p. 339) [63].
It appears that just a few protein phosphatases
suffice for the complicated regulation system of
protein phosphorylation and dephosphorylation
in the tissues of mammals. Four types of protein
serine/threonine phosphatases are known, of
which 1, 2A and 2B show significant mutual
homology, whereas 2 C belongs to another family.
The third family of protein phosphatases is that of
the protein tyrosine phosphatases [31]. The four
protein serine/threonine phosphatases may be
divided into two classes according to their catalytic and regulatory properties. Protein phosphatase 1 is specific for the ~-subunit in the reaction
with phosphorylase-b kinase and is inhibited by
two specific protein inhibitors 1 and 2. The three
enzymes belonging to the second class (2A, 2 B
and 2 C) are all specific for the phosphorylase-b