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Regulation of the cytoskeleton: an oncogenic function for cdk inhibitors?

Nature Reviews Cancer volume 4, pages 948–955 (2004)Cite this article

Key Points

  • Recent evidence points to cell-cycle independent functions for cyclin, cyclin-dependent kinases (CDKs) and CDK inhibitors (CKIs). In particular, the involvement of these proteins in the regulation of the cytoskeleton and cell migration is emerging.

  • In subsets of many human tumour types, the function of CKIs of the Cip/Kip family is altered by relocation to the cytoplasm, rather than through mutation like most other tumour suppressors. The cytoplasmic localization of p21 (CIP1) and p27 (KIP1) is associated with high tumour grade, tumour cell invasiveness and metastasis.

  • Whereas the function of CKIs as tumour suppressors is well characterized in the nucleus, they also seem to function in the cytoplasm, where they regulate cytoskeletal functions. This occurs through the modulation of the Rho signalling pathway. This cytoplasmic function could be oncogenic, as inhibition of the Rho pathway can result in increased migratory capacity.

  • p27 binds to RhoA and prevents the interaction of RhoA with its activators the guanine-nucleotide exchange factors. Fibroblasts lacking p27 have impaired migration. CIP1 binds to and inhibits Rho kinases (ROCK1 and -2) — downstream effectors of Rho. p57 (KIP2) binds to and targets LIM domain-containing protein kinase (LIMK) to the nucleus, sequestering it in a compartment where it cannot regulate the actin cytoskeleton.

  • Rho GTPases regulate the levels and timing of expression of cell-cycle regulators, and cell-cycle regulators also regulate Rho signalling.

  • The regulation of the cytoskeleton and cell migration by CKIs might contribute to the process of tumorigenesis. Targeting these functions of CKIs might therefore constitute a new therapeutic strategy.

Abstract

Cyclin-dependent kinase inhibitors (CKIs) are well known inhibitors of cell proliferation. Their activity is disrupted in many tumour types. Recent studies show that some of these proteins have interesting alternative functions, acting in the cytoplasm to regulate Rho signalling and thereby controlling cytoskeletal organization and cell migration. The upregulation of CKIs in the cytoplasm of many cancer cells indicates that although loss of nuclear CKIs is important for cancer cell proliferation, gain of cytoplasmic CKI function might be involved in tumour invasion and metastasis.

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Figure 1: Regulation of the cytoskeleton by Rho signalling.
Figure 2: Regulation of cyclin-dependent kinase inhibitors and cyclins by the Rho pathway.
Figure 3: Regulation of the Rho pathway and the cytoskeleton by cyclin-dependent kinase (CDK) inhibitors.

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Acknowledgements

We would like to apologize for not being able to cite all the relevant literature due to space limitations. A.B. is a Howard Hughes Medical Institute fellow of the Life Sciences Research Foundation. R.K.A. is supported by grants from the National Institutes of Health. J.M.R. is an investigator at the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Division of Basic Science, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Seattle, 98109, Washington, USA

    Arnaud Besson & James M. Roberts

  2. Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Richard K. Assoian

  3. Division of Basic Science, Fred Hutchinson Cancer Research Center, Mail stop A3-020, 1100 Fairview Avenue North, Seattle, 98109, Washington, USA

    James M. Roberts

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  1. Arnaud Besson
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Correspondence to James M. Roberts.

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Related links

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DATABASES

Entrez Gene

CCND1

CDC2

CDKN1A

CDKN1B

National Cancer Institute

breast cancer

cervical cancer

leukaemia

oesophageal cancer

uterine cancer

Swiss-Prot

ASK1

caldesmon

CDC42

CDK1

CDK4

CDK6

cyclin D1

Far1

KIS

LIMK1

mDIA

p14

p15

p16

p18

p19

p21

p27

Rac1

RhoA

SKP2

FURTHER INFORMATION

Assoian's homepage

Roberts' homepage

Glossary

GEF

Rho-family GTPases cycle between a GDP-bound inactive state, and a GTP-bound active state. Guanine-nucleotide exchange factors (GEFs) facilitate the exchange of GDP for GTP to generate the activated form of the GTPase, which in turn can interact with and activate its downstream effectors.

GAP

GTPase activating enzymes (GAPs) accelerate the intrinsic GTPase activity of Rho family members, returning the proteins to their inactive, GDP-bound state.

GDI

Guanine nucleotide dissociation inhibitors (GDIs) associate with the GDP-bound form of Rho-family proteins and control their cycling between the membrane and the cytosol.

F-BOX PROTEIN

F-box proteins are subunits of the SCF (Skp1–Cullin1–F box) class of E3 ubiquitin-protein ligases. F-box proteins are adaptors that bind both to protein substrates and to the Skp1–Cullin1 scaffold, and thereby determine the substrate specificity of the complex.

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Besson, A., Assoian, R. & Roberts, J. Regulation of the cytoskeleton: an oncogenic function for cdk inhibitors?. Nat Rev Cancer 4, 948–955 (2004). https://doi.org/10.1038/nrc1501

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