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SARA, Smads and the internalization process.They found that loss of cPML destroys TGF-�signalling, and began to dissect the molecularpathways that underpin the process. One sur-prise to come out of the work is that cPML isrequired for the interaction of Smads withSARA. This is puzzling because SARA canbind directly to Smads7, so why is cPML nec-essary for the interaction in vivo? Anotherremarkable result from the paper provides aclue: cPML also binds to TGF-� receptors andis required for the movement of both the TGF-�–receptor complex and SARA into the earlyendosome. One possible implication is that
SARA can only bind to Smads inside the endo-some, and that one role of cPML is to bring the two together. These findings suggest thatinterference with receptor localization andSARA–Smad interactions is the main mecha-nism by which loss of cPML abrogates cellularresponses to TGF-�.
The results raise lots of interesting ques-tions, an obvious one being: how does cPMLregulate the localization of receptors andSARA to the early endosome? Does it pro-mote the transfer of the TGF-� receptor intothe endosome; does it regulate the time thatthe receptor complex stays in the endosome;or does it control the targeting of SARA toearly endosomes? One hint at an answercomes from the observation that cPML has aRING-finger domain. In other cell-surface-located receptors, this domain mediatestheir trafficking by helping to attach a pro-tein tag called ubiquitin to them8. So, onefunction of cPML might be to promote theinternalization of the receptors.
The finding that cPML is required forTGF-� signalling also converges nicely withobservations that APL cell lines do notrespond to TGF-�2. APL is almost alwayslinked with a rearrangement of the genesencoding PML and the retinoic-acid recep-tor-� (RAR�). The outcome is a fusioninvolving one copy of the PML gene, whichproduces a PML–RAR� fusion protein; thishas aberrant activity2 and inhibits the activityof the normal PML in these tumours.
To wrap up their story, Lin et al. investiga-ted TGF-� resistance in APL cell lines thatcontain the PML–RAR� rearrangement.They confirmed that, in these cells, cPML–Smad complexes could not be detected andTGF-� treatment does not promote Smadactivation. By treating the cells with retinoicacid, which causes degradation of PML–RAR�, the authors reversed this effect, con-firming that PML–RAR� does indeed conferTGF-� resistance by interfering with normalcPML still present in the cell. Thus, the workalso touches on how the loss of functionalcPML might contribute to the ‘antisocial’behaviour of cancers that display resistanceto TGF-�. Moreover, it reveals a link betweenanomalies in trafficking events in the TGF-�system and alterations in the signalling prop-erties of cancer cells. ■
Christine Le Roy and Jeffrey L. Wrana are in theDepartment of Medical Genetics and Microbiology,University of Toronto, and the Program inMolecular Biology and Cancer, Samuel LunenfeldResearch Institute, Mount Sinai Hospital,600 University Avenue, Toronto M5G 1X5, Canada.e-mail: [email protected]. Siegel, P. M. & Massagué, J. Nature Rev. Cancer 3, 807–820 (2003).2. Lin, H.-K., Bergmann, S. & Pandolfi, P. P. Nature 431, 205–211
(2004).3. Salomoni, P. & Pandolfi, P. P. Cell 108, 165–170 (2002).4. Attisano, L. & Wrana, J. L. Science 296, 1046–1047 (2002).5. Di Guglielmo, G. M. et al. Nature Cell Biol. 5, 410–421 (2003).6. Tsukazaki, T. et al. Cell 6, 779–791 (1998).7. Wu, G. et al. Science 287, 92–97 (2000).8. Marmor, M. D. & Yarden, Y. Oncogene 11, 2057–2070 (2004).
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Cell biology
An unexpected social servantChristine Le Roy and Jeffrey L. Wrana
Cells communicate through signals that must be propagated from cellsurface to nucleus. Tracking the signals generated by the transforminggrowth factor-� protein reveals a surprising partner in this process.
During the development and main-tenance of multicellular organisms,cells spend a lot of time communica-
ting with each other to ensure that they arebehaving in an appropriate and harmoniousmanner. This ‘social’ behaviour is mediatedby the production of various signals outsidethe cell. These are interpreted in respondingcells by networks of signal-transductionproteins that regulate the appropriate cellu-lar response. One major class of signalsemitted by cells in all animals is the trans-forming growth factor-� (TGF-�) super-family of growth and differentiation factors,which control normal development and biological processes, as well as cancer pro-gression1. On page 205 of this issue, Lin andcolleagues2 report an unexpected participantin the network that interprets TGF-� familysignalling — cytoplasmic promyelocyticleukaemia protein (cPML).
PML is involved in a range of biologicalfunctions that include cell ageing, cell prolif-eration and programmed cell death3. As itsname suggests, when these functions are disrupted, the result is acute promyelocyticleukaemia (APL) — so PML is classed as atumour-suppressor protein. Most tumour-suppressing activities of PML are ascribed toits nuclear functions, but the function of thecytoplasmic form (cPML) was a mystery.Now it seems that it is a key accessory proteinin the transduction of TGF-� signals.
At the cell surface, TGF-� interacts withtwo receptor complexes that functiontogether to activate a downstream pathwayof signalling proteins called Smads (Fig. 1).Smads move to the nucleus, where they canmodulate cellular responses by regulatingthe expression of specific target genes4. Onemajor feature of cell signalling is that recep-tors at the cell surface are transported intothe cell, where they can either be recycledback to the cell surface,or be degraded.In thecase of TGF-� receptors, this internalizationtransfers some of the receptors into anorganelle called the early endosome — a process that is crucial for TGF-� signaltransduction in some cells5. The importanceof early endosomes in TGF-� signalling isprobably manifested by the presence of aprotein called SARA (for ‘Smad anchor ofreceptor activation’) that can bind to bothSmads and TGF-� receptors6.
Lin et al.2 report that cPML is crucial inorchestrating the dance that goes on during asignalling event, coordinating the receptors,
SARASARA
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142 NATURE | VOL 431 | 9 SEPTEMBER 2004 | www.nature.com/nature
Figure 1 Transforming growth factor-� (TGF-�)signalling. Lin et al.’s work2 suggests a role for thecytoplasmic form of promyelocytic leukaemiaprotein (cPML). At the cell surface, cPML mightinteract with the two TGF-� receptors (T�RI and T�RII) and act as a bridging factor betweenSARA and Smad2/3. Upon stimulation with TGF-�, cPML promotes the transfer of the complexcontaining T�RI, T�RII, SARA and Smad2 intoearly endosomes. There, cPML might dissociatefrom the complex (a), allowing Smad2/3 tointeract with SARA (b) and to be phosphorylated(c) by T�RI. Phosphorylated Smad2/3 moves intothe nucleus to propagate TGF-� signalling.
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© 2004 Nature Publishing Group
