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Plant Physiology 147:1560-1564 (2008) © 2008 American Society of Plant Biologists Plasma Membrane Receptor ComplexesLaboratory of Biochemistry, Department of Agrotechnology and Food Sciences, Wageningen University, Dreijenlaan 3, 6703 HA Wageningen, The Netherlands
Recent data on the plasma membrane (PM)-located LRR-RLKs (for Leu-rich repeat receptor-like kinases) BRI1 (for brassinosteroid insensitive 1) and the coreceptors BAK1 (for BRI1-associated kinase 1) and SERK1 (for somatic embryogenesis receptor-like kinase 1) that participate in the perception of brassinosteroids (BRs) suggest that they are organized into heterooligomeric protein complexes. Other components of this complex include members of the 14-3-3 family, and, in the case of SERK1, the kinase-associated protein phosphatase (KAPP) and the AAA ATPase cell division cycle 48A (CDC48A). CDC48 proteins interact with ubiquitinated target proteins in animal and plant cells. In this Update we describe the role of several of the nonreceptor partners of the PM receptor complex with an emphasis on the role of CDC48 proteins in translocation and ubiquitination as a proposed mode of regulation of plant PM receptors.
Receptors such as BRI1 and SERK1 are synthesized in the endoplasmic reticulum (ER), from where they pass through the Golgi network to be inserted into the PM. Indeed, the use of fluorescently tagged BRI1 and SERK proteins has shown clearly both plasma and internal membrane localization (Li and Chory, 1997  ; Li et al., 2002; Nam and Li, 2002; Russinova et al., 2004; Albrecht et al., 2005; Kwaaitaal et al., 2005). In Arabidopsis (Arabidopsis thaliana), removal of receptors from the PM by endocytosis is documented for BRI1, BAK1, SERK1, and the flagellin-sensing receptor FLS2 (Russinova et al., 2004; Chinchilla et al., 2007; Geldner et al., 2007). In the case of FLS2, ligand-induced endocytosis was documented (Robatzek et al., 2006; Chinchilla et al., 2007) while the BRI1 and SERK receptors seem to undergo non-ligand-dependent recycling (Russinova et al., 2004; Geldner et al., 2007). The SERK1 protein is one of five members of a small family belonging to subgroup II of the LRR-RLKs in Arabidopsis. SERK1, together with SERK2, is instrumental in male fertility (Albrecht et al., 2005) while SERK3, also known as BAK1, forms a heterodimer with BRI1 (Li et al., 2002; Nam and Li, 2002). Upon binding of BR to the extracellular domain of BRI1, the BRI1 kinase inhibitor 1 (BKI1), a negative regulator of BRI1 activity, is released from the PM and increases the affinity of BRI1 for BAK1/SERK3 (Wang and Chory, 2006; Fig. 1
). Oligomerization of the BRI1/BAK1 receptors and transphosphorylation of the kinase domains takes place (Wang et al., 2005; Wang and Chory, 2006). This inhibits, via an unknown pathway, the phosphorylation of BZR1 (for brassinazole resistant 1) by the BIN2 (for BR insensitive 2) kinase that, when phosphorylated, is translocated to (Ryu et al., 2008) and retained in the cytoplasm via 14-3-3 proteins (Gampala et al., 2007). Moreover, BR activates the phosphatase BSU1 (for BRI1 suppressor protein 1) that dephosphorylates BES1 (for BRI1 EMS suppressor 1). Subsequently, accumulation of dephosphorylated nuclear-localized BES1 and dephosphorylated BZR1 transcription factors induces the genetic response to brassinolide in Arabidopsis. BAK1/SERK3 alone also serves a BR-independent pathway involved in plant immunity (Heese et al., 2007; Kemmerling et al., 2007), interacts with FLS2 (Chinchilla et al., 2007), and together with SERK4 is involved in cell death (He et al., 2007). BAK1/SERK3 is not the only coreceptor of BRI1; SERK1 also interacts with BRI1 (Karlova et al., 2006), and evidence has been presented that BKK1 (for BAK1-like kinase 1), identical to SERK4, also participates in BR signaling (He et al., 2007). Thus, the classical model for ligand-induced heterooligomerization followed by auto- and transphosphorylation as well as translocation of target proteins appears to apply to receptors of the BRI1/SERK class while complexes of different composition may have different specificity. So far no ligands have been shown to interact with the SERK receptors. Where and how the receptors and interacting proteins such as BKI1 are assembled into functional units have not been described so far. Structural elements involved in sorting of animal receptors such as Yxx and di-Leu motifs, involved in clathrin-mediated processes (Ortiz-Zapater et al., 2006), are found in the primary sequences of all receptors mediating the BR response, suggesting complex sorting and trafficking pathways.
The SERK1 complex was immunoprecipitated from transgenic seedlings and found to contain both the BRI1 and SERK3 proteins. In addition were identified the KAPP protein, a member of the 14-3-3 family, and the AAA ATPase CDC48A (Fig. 2 ), as well as two putative transcriptional regulators. Of these the KAPP, 14-3-3, and CDC48A proteins also were found previously in a yeast two-hybrid screening (Rienties et al., 2005 ), suggesting a direct interaction with the SERK1 receptor. In mammalian cells, the CDC48A ortholog p97/VCP is phosphorylated by the JAK-2 kinase and dephosphorylated by PTPH1 that in turn is associated with a 14-3-3 protein (Zhang et al., 1999; Lavoie et al., 2000). The interaction between KAPP and SERK1 is dependent on the phosphorylation status of the Thr residues in the SERK1 activation loop. In vitro, KAPP not only dephosphorylates SERK1 but also actively prevents autophosphorylation of the receptor, possibly maintaining the dephosphorylated state of SERK1 (Shah et al., 2002). In cells, KAPP colocalizes at the PM and in the cytoplasm in endosomal compartments with SERK1 and colocalizes with the endosomal marker Ara6 and the membrane dye FM4-64 (Aker et al., 2006). In contrast, CDC48A does not colocalize with SERK1 in endosomal compartments but colocalizes and interacts with SERK1 in ER-membrane-based regions in close proximity to the PM (Aker et al., 2006). It is still unclear if CDC48A and KAPP can interact directly, suggesting that the three plant proteins may not be a direct copy of the corresponding animal complexes.
After activation of animal receptor complexes, changes in interacting partners and/or location often occur. Members of the regulatory 14-3-3 family of proteins were shown to be instrumental in protein translocation between the cytosol and the nucleus in animal cells (Aitken, 2006 ). In Arabidopsis BR signaling it was shown that 14-3-3 retains phosphorylated BZR1 in the cytoplasm, thereby preventing pBZR1 degradation and inhibiting BR-induced gene expression (Gampala et al., 2007). Likewise, in human cells, 14-3-3 is up-regulated by the tumor suppressor gene p53 in response to DNA damage and retains the E3 ubiquitin ligase murine double minute oncogene (MDM2) in the cytoplasm, thereby preventing p53 degradation and inhibiting tumor growth (Yang et al., 2007).
SERK1 also contains a putative 14-3-3 binding domain, RPPS394QPP, and was shown to interact with 14-3-3 To summarize, these data suggest that not all the proteins identified are part of the same SERK1-containing complex and therefore can represent different stations during the trafficking of SERK1 through the cell.
Turnover of receptors and other membrane proteins is dependent on endocytosis and/or ubiquitin-mediated protein degradation via the proteasome pathway. Monoubiquitination serves as a signal for endocytosis of PM proteins, sorting of proteins to the multivesicular bodies (MVBs), budding of retroviruses, DNA repair, and transcriptional activation. Polyubiquitination has been associated mainly with targeting substrates to the proteasome (for review, see Haglund et al., 2003 ).
Examples of trafficking of cell surface molecules mediated by ubiquitin is the recruitment of G-protein-coupled receptors (GPCRs) and other cargo into vesicles budding from either the PM or the MVB (Reggiori and Pelham, 2001
In plant receptor biology only a few cases have been described that suggest involvement of ubiquitination in membrane protein trafficking. Internalization of plant-specific auxin efflux carriers (PIN proteins) in the PM is required for the regulation of auxin efflux (Geldner et al., 2003
One partner of the BRI1/SERK receptor complex possibly involved in regulation of the SERK1 receptor degradation is the AAA ATPase CDC48A.The yeast and animal homologous proteins CDC48 and p97 are involved in various activities as diverse as cell cycle regulation, transcriptional activation, membrane fusion, and ER-associated degradation (ERAD) of misfolded proteins (Woodman, 2003 ; Müller et al., 2005). Although the ATPases also are involved in proteasome-independent functions, many substrates of CDC48 proteins eventually are degraded in the proteasome. Polyubiquitinated substrates are delivered to the proteasome via ubiquitin receptors that bind to the ubiquitin moiety and the proteasome. Most cofactors of p97/CDC48 also bind to ubiquitin conjugates, whether they are associated with proteolytic activity or not. This suggests that ubiquitination is a common regulator in various functions of p97/CDC48 and does not result in proteolytic degradation by default (Ye, 2006).
Meyer et al. (2000)
Similar to the situation in yeast (http://www.yeastgenomics.org/), also in Arabidopsis CDC48 proteins are found to be interacting with a large variety of different proteins, such as ubiquitin-binding proteins, SNARE proteins, including the cell plate-associated protein KNOLLE, as well as SYP21 and SYP31 (Rancour et al., 2002
CDC48 proteins were shown to be involved in proteasomal targeting of proteins. Proteasome activity has been shown to mediate turnover of plant membrane proteins including PIN2. Treatment of PIN2 seedlings with the proteasome inhibitors MG132 and lactastatin resulted in elevated PIN2 levels. Furthermore, proteasome inhibition caused a dramatic increase in the amount of ubiquitinated PIN2 (Abas et al., 2006 ).
Proteasome-dependent turnover of SERK1 receptors might be a way to regulate its activity. CDC48A may be involved in targeting polyubiquitinated receptors for degradation in the proteasome, like it was shown for the mammalian cytokine receptors IL-2 and IL-9, the erythropoietin receptor, and the CDC48 homolog p97 (Yen et al., 2000
Recent evidence from animal receptor biology suggests that ubiquitination is one of the first biochemical events after receptor activation (Lowe et al., 2006 ; Shenoy, 2007) and therefore also could be involved in later steps in plant signaling pathways via PM LRR-RLKs. We propose that the AAA ATPase protein CDC48A interacts with the SERK receptor as a chaperone to promote the formation of correctly folded receptors in the ER and to remove misfolded proteins by degradation via the ubiquitin-proteasome pathway. In Figure 2 the possible degradation pathways of the SERK1 receptor after activation are depicted. Received April 3, 2008; accepted May 22, 2008; published August 6, 2008.
The author responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (www.plantphysiol.org) is: Sacco C. de Vries (sacco.devries{at}wur.nl). www.plantphysiol.org/cgi/doi/10.1104/pp.108.120501 * Corresponding author; e-mail sacco.devries{at}wur.nl.
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THE BRI1/SERK RECEPTOR COMPLEX
DIFFERENT SERK1 RECEPTOR...
(Rienties et al., 2005
