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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 127

Module 2: Figure sterol sensing

Sterol signalling at the endoplasmic reticulum (ER) membrane.
Sterols bind to the sterol regulatory element-binding proteins (SREBP) cleavage-activating protein (SCAP) resulting in the activation of site-1 protease
(S1P), which then cleaves the SREBPs at a point on the luminal loop. A site-2 protease (S2P) then hydrolyses the N-terminal bHLH (basic helix–
loop–helix) fragment to release the cytosolic portion, which then diffuses into the nucleus to initiate gene transcription. Reproduced from Brown, M.S.
and Goldstein, J.L. (1999) A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc. Natl. Acad. Sci. U.S.A.
96:11041–11048. Copyright (1999) National Academy of Sciences, U.S.A.; see Brown and Goldstein 1999).

transcription factors dimerize through a basic loop--helix-- Rossman, K.L., Der, C.J. and Sondek, J. (2005) GEF means go: turning
leucine zipper and enter the nucleus, where they bind to on Rho GTPases with guanine nucleotide-exchange factors. Nat. Rev.
Mol. Cell. Biol. 6:167–180.
sterol regulatory elements on the genes that code for the
Somlyo, A.P. and Somlyo, A.V. (2003) Ca 2 + sensitivity of smooth muscle
enzymes of lipid biosynthesis (cholesterol, unsaturated and nonmuscle myosin II: modulated by G proteins, kinases, and
fatty acids and triacylglycerols) and lipid-uptake mech- myosin phosphatase. Physiol. Rev. 83:1325–1358.
Tybulewicz, V.L.J. (2005) Vav-family proteins in T-cell signalling. Curr.
anisms. The sterol sensor is a SREBP cleavage-activating
Opin. Immunol. 17:267–274.
protein (SCAP). When sterols build up in the membranes, Welch, H.C.E., Coadwell, W.J., Stephens, L.R. and Hawkins, P.T. (2003)
they bind to SCAP to inhibit the proteolytic cleavage Phosphoinositide 3-kinase-dependent activation of Rac. FEBS Lett.
546:93–97.
of the SREBPs. The ER thus plays a central role both
in sensing the level of sterols and then providing the
output signals that make the necessary adjustments to
lipid synthesis to maintain a constant level of membrane Cyclic AMP signalling pathway
cholesterol. Cooper, D.M. (2003) Regulation and organization of adenylyl cyclases
and cAMP. Biochem. J. 375:517–529.
Whorton, M.R. and Sunahara, R.K. (2003) Adenylyl cyclases. In
Handbook of Cell Signaling, Vol. 2 (Bradshaw, R.A. and Dennis, E.A.,
eds), pp. 419–426, Academic Press, San Diego.
References

Monomeric G proteins
Cullen, P.J. and Lockyer, P.J. (2002) Integration of calcium and Ras G proteins
signalling. Nat. Rev. Mol. Cell Biol. 3:339–348. Feig, L.A. (2003) Ral-GTPase: approaching their 15 minutes of fame.
Manser, E. (2003) Cytoskeletal regulation: small G-protein–kinase Trends Cell Biol. 13:419–425.
interactions. In Handbook of Cell Signaling, Vol. 1 (Bradshaw, R.A. Myers, K.R. and Casanova, J.E. (2008) Regulation of actin cytoskeleton
and Dennis, E.A., eds), pp. 499–503, Academic Press, San Diego. dynamics by Arf-family GTPases. Trend Cell Biol. 18:184–192.
Mitlin, N., Rossman, K.L. and Der, C.J. (2005) Signalling interplay in Ras Stenmark, H. (2009) Rab GTPases as coordinators of vesicle traffic. Nat.
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