PTENlike Domains as Possible Targets of Lipid Signalling

Proteins of the PTEN superfamily are emerging as candidates for a link between signalling lipids, in particular PI(3,4,5)P3(PIP3), and downstream effectors. The PTEN molecule exhibits structural similarity to dual specificity protein phosphatases, contains the protein phosphatase active site signature, HCXXGXXR, and possesses a phosphatase activity towards both lipids and proteins. However, its protein tyrosine phosphatase activity is rather weak, compared to the strong affinity towards PIP3 (Li and Sun 1997).

Gupta et al. (2002) identified three PTEN homologues in the Arabidop-sis genome and demonstrated that one of them, AtPTEN1 (At5g39400), exhibits a lipid- and protein-phosphatase activity similar to the mammalian prototype. The failure to isolate T-DNA insertion mutants in AtPTEN1 suggested that the gene might be essential, which led the authors to construct "knock-down" Arabidopsis lines using the RNAi technology. They found that AtPTEN1 depletion results in loss of pollen viability, which is consistent with the observed pollen-specific activity of the AtPTEN1 promoter. The affected pollen grains revealed cell surface defects, namely local separation of plasma membrane from the intine, as well as both intine and exine lesions, again supporting possible role of PTEN in development of surface structures of the pollen grain. Interestingly, the AtPTEN proteins (and their relatives from other species) are not the only representatives of the PTEN superfamily in the plant kingdom. A divergent PTEN-related domain is present in the variable N-terminal extension of many plant formins (Cvrckova et al. 2004b), i.e., members of the formin (FH2 protein) family.

Higher plants have a prolific family of FH proteins (encoded by 21 loci in Arabidopsis). Plant formins can be divided into two distinct subfamilies (classes) based on the sequence of the conserved FH2 domain (Cvrckova et al. 2004a; Deeks et al. 2002). Presence of PTEN-like domains is characteristic for Class II plant formins, while most Class I proteins carry a N-terminal membrane-insertion signal (Cvrckova 2000), suggesting a possible plant-specific mechanism of cytoskeleton-membrane connection. No functional studies on Class II formins have been reported so far. It is not even known yet whether Class I and Class II FH2 proteins can form mixed heterodimers, which would greatly increase the diversity of formin complexes and their regulation. In Arabidopsis pollen, only three Class II formins (AtFH13, AtFH14 and AtFH17) are expressed to a significant extent (data from Honys and Twell 2004 and Pina et al. 2005); two of them, AtFH13 and AtFH14, possess the PTEN-related domain.

The only available knowledge on the PTEN-like domain present in many Class II formins results from bioinformatic analyses of a collection of the four domains of Arabidopsis formins AtFH13, AtFH14, AtFH18 and AtFH20, as well as related sequences from rice and Medicago truncatula (Cvrckova et al. 2004a). Surprisingly, all these formin-associated PTEN domains contain mutations that make catalytic activity as either lipid or protein phosphatase extremely unlikely. A crucial arginine residue in the phosphatase active site is replaced by hydrophobic or small polar residues in the plant proteins, and a conserved and functionally important asparagine is substituted by glycine. We therefore believe that the function of plant PTEN domains is rather structural than catalytic - perhaps analogous to the role of the transmembrane segments in Class I formins. A variant PTEN domain that lacks catalytic activity but retains its intracellular phospholipids-dependent localization ability might contribute to intracellular positioning of the actin-organizing FH2 domains. Such a structural role could perhaps be attributed to the C-terminal portion of the conserved PTEN core, which is related to a class of domains collectively referred to as C2; curiously, this portion appears to be lost in the AtPTEN proteins, while it has been retained in the formin-associated PTEN domains, albeit in a highly diverged form (Cvrckova et al. 2004a; Gupta et al. 2002). The C2 domains found in PTEN-like part of plant formins resemble the C2 domain of human PTEN, including the residues that make PTEN Ca2+ independent.

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