Insights into the evolution of the ErbB receptor family and their ligands from sequence analysis - PubMed (original) (raw)
Insights into the evolution of the ErbB receptor family and their ligands from sequence analysis
Richard A Stein et al. BMC Evol Biol. 2006.
Abstract
Background: In the time since we presented the first molecular evolutionary study of the ErbB family of receptors and the EGF family of ligands, there has been a dramatic increase in genomic sequences available. We have utilized this greatly expanded data set in this study of the ErbB family of receptors and their ligands.
Results: In our previous analysis we postulated that EGF family ligands could be characterized by the presence of a splice site in the coding region between the fourth and fifth cysteines of the EGF module and the placement of that module near the transmembrane domain. The recent identification of several new ligands for the ErbB receptors supports this characterization of an ErbB ligand; further, applying this characterization to available sequences suggests additional potential ligands for these receptors, the EGF modules from previously identified proteins: interphotoreceptor matrix proteoglycan-2, the alpha and beta subunit of meprin A, and mucins 3, 4, 12, and 17. The newly available sequences have caused some reorganizations of relationships among the ErbB ligand family, but they add support to the previous conclusion that three gene duplication events gave rise to the present family of four ErbB receptors among the tetrapods.
Conclusion: This study provides strong support for the hypothesis that the presence of an easily identifiable sequence motif can distinguish EGF family ligands from other EGF-like modules and reveals several potential new EGF family ligands. It also raises interesting questions about the evolution of ErbB2 and ErbB3: Does ErbB2 in teleosts function differently from ErbB2 in tetrapods in terms of ligand binding and intramolecular tethering? When did ErbB3 lose kinase activity, and what is the functional significance of the divergence of its kinase domain among teleosts?
Figures
Figure 1
Phylogenetic relationship of the EGF modules from the invertebrate ErbB ligands. This tree was generated using neighbor joining with poisson correction of protein sequences in MEGA version 3.1 [61]. Some of the bootstrap percentages for the various branch points are shown.
Figure 2
Consensus sequences for the mammalian ligands. Alignment was generated in ClustalX [60]. To minimize errors in amino acid sequence from the DNA sequences used in the analysis, a conserved residue was called conserved if it was in at least 75% of the sequences for an individual ligand. In the alignment, gaps are denoted by a dash (-) and non-conserved residues are indicated by an X. Reverse text (white text on black background) denotes residues that are at least 75% conserved among the different ligands, with grey shaded text (black text on grey background) denoting residues that are different at these conserved positions. Shown for comparison at the bottom is the sequence of human EGF and numbering for the mature ligand.
Figure 3
Phylogenetic relationship of the EGF modules from the vertebrate ErbB ligands. The tree shown was generated using neighbor joining with poisson correction of protein sequences in MEGA version 3.1 [61]. Each colored oval highlights the cluster of branches for a different ligand. Shown are some of the bootstrap percentages for the split between the two ligand families. Though the bootstrap percentages show low confidence in some of the branches of the tree, trees generated using different methods of distance correction exhibited similar separation of EGF receptor ligands and ErbB3/ErbB4 ligands and the positions of ligands relative to each other were comparable. Similar trees were generated using the Phylip [62] group of programs.
Figure 4
Detailed trees for the AR/HB-EGF and TR1/TR2 pairs. (A) The AR/HB-EGF pair from the tree in Fig. 3. HB-EGF exists in both teleosts and tetrapods, but there is no teleost AR, while the teleosts do have a second sequence labeled AHP, which is slightly more similar to HB-EGF than to AR. (B) The TR1/TR2 pair from the tree in Fig. 3. This tree shows an additional duplication pattern with both TR1 and TR2 forms in the teleosts segregating together. This tree is complicated by the different ligand length for TR2 in the teleosts compared to the rest of the ligands on this branch. The difference in length does suggest an alteration in the sequence requirement for TR2 in the teleosts. (C) Tomoregulin 1 and 2 sequences from human and zebrafish. These sequences are representative of the sequences from other species. TR2 is two amino acids shorter in the zebrafish than the other sequences. Reverse text (white text on black background) denotes residues that are at least 75% conserved between the four ligands, with grey shaded text (black text on grey background) denoting residues that are different at these conserved positions.
Figure 5
Consensus sequences for the teleost and tetrapod ErbB receptors. The alignment was generated in ClustalX [60]. To minimize errors in amino acid sequence from the DNA sequences used in the analysis, a conserved residue was called conserved if it was in 75% of the sequences. In the alignment, gaps are denoted by a dash (-) and non-conserved residues are indicated by an X. Reverse text (white text on black background) denotes residues that are at least 75% conserved between the different ligands, with grey shaded text (black text on grey background) denoting residues that are different at these conserved positions. The color bars along the top denote different subdomains within the receptor: red, subdomain I; magenta, subdomain II; green, subdomain III; cyan, subdomain IV; yellow, transmembrane; blue, intracellular juxtamembrane domain; and orange, kinase domain. The sequences start at the beginning of the second exon, and the residue numbers are for the human receptors. The regions or residues of interest are: (A) extended regions that are not well conserved in ErbB2 sequences; (B) extracellular juxtamembrane region that is alternatively spliced in ErbB4 yielding a long and short form; (C) the one glycosylation site that is conserved in the four receptors; (D) regions in the kinase domain where ErbB3 differs relative to the other three receptors, corresponding to the C-helix (D1) and the activation loop (D2); (E) the C-terminal portion of the kinase domain that has receptor-specific sequences and has been shown to be involved in mediating high affinity binding; (#) residue involved in subdomain II-subdomain II interactions in the receptor dimer and subdomain II-subdomain IV interactions in the tethered receptor monomer; (&) and (*) residues involved in subdomain II-subdomain II interactions in the receptor dimer; (+) residues involved in subdomain II-subdomain IV interactions in the tethered receptor monomer; and (^) residues that interact with ligand.
Figure 6
Phylogenetic relationship of the ErbB receptors. Shown is a tree generated using neighbor joining with p-distance correction of protein sequences in MEGA version 3.1 [61]. Shown are the bootstrap percentages for the split between invertebrate and vertebrate receptors. Similar trees were generated using different methods of distance correction. The invertebrate receptors lead into the vertebrate receptors separating ErbB3 and ErbB4 from EGF receptor and ErbB2. This structure suggests three gene duplication events, depicted by the filled circles, the first generating EGF receptor/ErbB2 and ErbB3/ErbB4 progenitors. Two more gene duplication events generated the four receptors seen in the vertebrates.
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