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Molecular and Cellular Biology, June 2001, p. 3750-3762, Vol. 21, No. 11
CRC Centre for Cell and Molecular Biology,
Chester Beatty Laboratories, Institute of Cancer Research, London
SW3 6JB, United Kingdom
Received 6 November 2000/Returned for modification 12 December
2000/Accepted 9 March 2001
TC21 is a member of the Ras superfamily of small GTP-binding
proteins that, like Ras, has been implicated in the regulation of
growth-stimulating pathways. We have previously identified the
Raf/mitogen-activated protein kinase pathway as a direct TC21 effector
pathway required for TC21-induced transformation (M. Rosário,
H. F. Paterson, and C. J. Marshall, EMBO J. 18:1270-1279, 1999). In this study we have identified two further effector pathways for TC21, which contribute to TC21-stimulated transformation: the
phosphatidylinositol 3' kinase (PI-3K) and Ral signaling pathways. Expression of constitutively active TC21 leads to the activation of Ral
A and the PI-3K-dependent activation of Akt/protein kinase B. Strong
activation of the PI-3K/Akt pathway is seen even with very low levels
of TC21 expression, suggesting that TC21 may be a key small
GTPase-regulator of PI-3K. TC21-induced alterations in cellular
morphology in NIH 3T3 and PC12 cells are also PI-3K dependent. On the
other hand, activation of the Ral pathway by TC21 is required for
TC21-stimulated DNA synthesis but not transformed morphology. We show
that inhibition of Ral signaling blocks DNA synthesis in human tumor
cell lines containing activating mutations in TC21, demonstrating for
the first time that this pathway is required for the proliferation of
human tumor cells. Finally, we provide mechanisms for the activation of
these pathways, namely, the direct in vivo interaction of TC21 with
guanine nucleotide exchange factors for Ral, resulting in their
translocation to the plasma membrane, and the direct interaction of
TC21 with PI-3K. In both cases, the effector domain region of TC21 is
required since point mutations in this region can interfere with
activation of downstream signaling.
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.11.3750-3762.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Activation of the Ral and Phosphatidylinositol 3'
Kinase Signaling Pathways by the Ras-Related Protein TC21
*
Corresponding author. Mailing address: CRC Centre for
Cell and Molecular Biology, Chester Beatty Laboratories, Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, United Kingdom. Phone:
44-20 7352 9772. Fax: 44-20 7352 5630. E-mail:
chrism{at}icr.ac.uk.
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