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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 112

Mutations of the Fz4 receptor, which activates this it can also be activated by certain growth factors (insulin,
Wnt/Ca 2 + pathway, have been linked to familial exud- IGF-I and EGF).
ative vitreoretinopathy (FEVR).

Casein kinase I (CKI) Hedgehog signalling pathway
The casein kinase I (CKI) family has seven members The Hedgehog signalling pathway in mammals closely re-
(CKIα, α2, δ, ε, γ1, γ2and γ3), which can have very sembles that originally discovered and characterized in
different functions in cells.
Drosophila. The mammalian Hedgehog signalling toolkit
has many of the components found in insects. In compar-
Casein kinase Iα and α2 ison with the latter, however, much less is known about
CKIα functions as a priming kinase for glycogen synthase the mechanism of Hedgehog activation of transcription in
kinase-3β (GSK-3β) during the operation of the Wnt sig- mammals. There are multiple Hedgehog signalling func-
nalling pathway (Module 2: Figure Wnt canonical path- tions that operate during both development and adult life.
way).

Casein kinase Iδ Hedgehog signalling toolkit
Casein kinase Iδ (CKIδ), which is 97% homologous with The Hedgehog signalling pathway has a number of com-
casein kinase Iε (CKIε), contributes to the operation of ponents (Module 2: Table Hedgehog signalling toolkit)
the circadian clock by phosphorylating PER1 and PER2 whose names resemble those given to similar components
to control the nuclear entry and stability of these clock pro- in Drosophila, where this signalling system was origin-
teins (Module 6: Figure circadian clock molecular mech- ally identified and characterized. While many of the mam-
anism). malian components have similar functions to those found
in insects, it is clear that there are important differences.
Since there are mammalian components that are not found
Casein kinase Iε
CKIε participates in circadian rhythmicity by phos- in insects, the mechanism of Hedgehog activation of tran-
phorylating the PER and CRY proteins to regulate their scription has to be worked out separately for vertebrates.
nuclear entry and stability during the operation of the
PER regulatory loop (Module 6: Figure circadian clock Hedgehog activation of transcription
molecular mechanism). Mutation of CKIε, which results Hedgehog mediates its effects by activating gene tran-
in a decrease in the ability of this kinase to phosphorylate
scription. Hedgehog uses mechanism 2 of the different
the PER proteins of the circadian clock, is responsible for transcription factor activation mechanisms found in cells
familial advanced sleep phase syndrome (FASPS).
(Module 4: Figure transcription factor activation). There
are three Hedgehog transcription factors (GLI 1--3), which
Casein kinase Iγ1, γ2and γ3 are held in an inactive state within the cytoplasm in rest-
CKIγ is an unusual member of the family in that it has ing cells (Module 2: Figure Hedgehog signalling pathway).
a palmitoylation site at its C-terminus and this fatty acid This inactive state is maintained by the Hedgehog receptor
anchor attaches it to the plasma membrane. This membrane patched (PTC), which inhibits the seven-membrane-
location is critical for one of its main functions, which is spanning protein smoothened (SMO) that acts as the
to phosphorylate the frizzled lipoprotein receptor-related Hedgehog transducer. In the absence of a signal from
protein (LRP) co-receptor LRP5/6 during activation of the SMO, the GLI transcription factors are maintained in a lat-
Wnt signalling pathway (Module 2: Figure Wnt canonical ent state by interacting with a large number of cytoplasmic
pathway). factors (Module 2: Table Hedgehog signalling toolkit). The
precise function of all these factors is still being worked
Casein kinase II (CK2) out. Hedgehog arriving at the cell surface induces a train of
Casein kinase II (CK2) is a serine/threonine protein kinase. events that activate these transcription factors so that they
It functions as a heterotetramer consisting of two 44 kDa translocate into the nucleus to induce gene transcription
catalytic α-subunits and two regulatory β-subunits. It has (Module 2: Figure Hedgehog signalling pathway). First of
a unique ability to use GTP as well as ATP as a phosphate all, Hedgehog binds to its receptor PTC and this removes
donor. CK2 is also known as phosvitin kinase, glycogen the inhibitory effect of PTC on SMO. The latter is then
synthase kinase 5, troponin T kinase and casein kinase G, able to activate GLI by removing it from the inhibitory
which reflects the fact that CK2 can phosphorylate many constraints of the cytoplasmic factors so that it is now free
different substrates and thus contributes to many control to translocate into the nucleus to activate transcription.
mechanisms. This multifunctional kinase has been implic- Some of the genes that are activated are components of the
ated in many cellular processes and seems to be particu- Hedgehog signalling pathway and thus set up both posit-
larly active in controlling cell proliferation and has also ive and negative feedback loops. Many of the other genes
been implicated in cell transformation and tumorigenesis. contribute to Hedgehog signalling functions.
Many of its actions depend on its ability to phosphorylate Expression of the GLI1 transcription factor is sup-
transcription factors such as Myc, p53, Rb and activating pressed by miR-324-5p. Mutations in miR-324-5p result
protein 1 (AP-1). Although CK2 is constitutively active, in the development of medulloblastomas.

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