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John P Cannon

Publications and source records attributed to John P Cannon.

11 recordsLinked to original sources
PubMed2006

Ancient evolutionary origin of diversified variable regions demonstrated by crystal structures of an immune-type receptor in amphioxus.

Although the origins of genes encoding the rearranging binding receptors remain obscure, it is predicted that their ancestral forms were nonrearranging immunoglobulin-type domains. Variable region-containing chitin-binding proteins (VCBPs) are diversified immune-type molecules found in amphioxus (Branchiostoma floridae), an invertebrate that diverged early in deuterostome phylogeny. To study the potential evolutionary relationships between VCBPs and vertebrate adaptive immune receptors, we solved the structures of both a single V-type domain (to 1.15 A) and a pair of V-type domains (to 1.85 A) from VCBP3. The deduced structures show integral features of the ancestral variable-region fold as well as unique features of variable-region pairing in molecules that may reflect characteristics of ancestral forms of diversified immune receptors found in modern-day vertebrates.

Animals↗
PubMed2006

Ancient divergence of a complex family of immune-type receptor genes.

Multigene families of activating/inhibitory receptors belonging to the immunoglobulin superfamily (IgSF) regulate immunological and other cell-cell interactions. A new family of such genes, termed modular domain immune-type receptors (MDIRs), has been identified in the clearnose skate (Raja eglanteria), a phylogenetically ancient vertebrate. At least five different major forms of predicted MDIR proteins are comprised of four different subfamilies of IgSF ectodomains of the intermediate (I)- or C2-set. The predicted number of individual IgSF ectodomains in MDIRs varies from one to six. MDIR1 contains a positively charged transmembrane residue and MDIR2 and MDIR3 each possesses at least one immunoreceptor tyrosine-based inhibitory motif in their cytoplasmic regions. MDIR4 and MDIR5 lack characteristic activating/inhibitory signalling motifs. MDIRs are encoded in a particularly large and complex multigene family. MDIR domains exhibit distant sequence similarity to mammalian CMRF-35-like molecules, polymeric immunoglobulin receptors, triggering receptors expressed on myeloid cells (TREMs), TREM-like transcripts, NKp44 and FcR homologs, as well as to sequences identified in several different vertebrate genomes. Phylogenetic analyses suggest that MDIRs are representative members of an extended family of IgSF genes that diverged before or very early in evolution of the vertebrates and subsequently came to occupy multiple, fully independent distributions in the present day.

Amino Acid Sequence↗
PubMed2005

Variable domains and a VpreB-like molecule are present in a jawless vertebrate.

Immunoglobulins (Igs) and T cell antigen receptors (TCRs) that undergo somatic diversification have not been identified in the two extant orders of jawless vertebrates, which occupy essential positions in terms of understanding the evolution of the emergence of adaptive immunity. Using a single motif-dependent PCR-based approach coupled with a vector that allows selection of cDNAs encoding secretion signal sequences, four different genes encoding Ig V-type domains were identified in the sea lamprey (Petromyzon marinus). One of the predicted proteins encoded by these genes shares structural characteristics with mammalian VpreB molecules, including the absence of a recognizable transmembrane region, a relatively high proportion of charged amino acids in its C-terminal tail and distinctive features of its secretion signal peptide. This is the first indication of a molecule related to the B cell receptor (BCR) complex in a species that diverged prior to the jawed vertebrates in which RAG-mediated adaptive immunity is first encountered.

Amino Acid Sequence↗
PubMed2005

New insights into alternative mechanisms of immune receptor diversification.

The clonal commitment, selection, and expansion of B and T lymphocytes expressing diversified receptors provide the underlying basis for the jawed vertebrates adaptive immune response. At the core of this process is the rearrangement and somatic modification of segmental genetic elements that encode the constituent components of immunoglobulins and T-cell antigen receptors. No evidence has been found for a similar mechanism outside of jawed vertebrates; however, invertebrates and jawless vertebrates are subjected to continuous exposure to pathogenic bacteria, viruses, and parasites. The invertebrates and jawless vertebrates as well as jawed vertebrates all encode a variety of mediators of innate immunity. Several reports of extensive germline diversification of conventional innate receptors, as well as molecules that resemble innate receptors but undergo germline and somatic modification, have been made recently. The range of such molecules, which include the fibrinogen-related proteins (FREPs) in a mollusc, variable region-containing chitin-binding proteins (VCBPs) in a cephalochordate, variable lymphocyte receptors (VLRs) in jawless vertebrates, and novel immune-type receptors (NITRs) in bony fish, encompasses both the immunoglobulin gene superfamily (IgSF) and leucine-rich repeat (LRR) proteins. Although these molecules vary markedly in form and likely in function, growing evidence suggests that they participate in various types of host defense and thereby represent significant alternatives to current paradigms of innate and adaptive immune receptors. Unusual genetic mechanisms for diversifying recognition proteins may be a widespread characteristic of animal immunity.

Adaptation, Physiological↗
PubMed2005

Reconstructing immune phylogeny: new perspectives.

Numerous studies of the mammalian immune system have begun to uncover profound interrelationships, as well as fundamental differences, between the adaptive and innate systems of immune recognition. Coincident with these investigations, the increasing experimental accessibility of non-mammalian jawed vertebrates, jawless vertebrates, protochordates and invertebrates has provided intriguing new information regarding the likely patterns of emergence of immune-related molecules during metazoan phylogeny, as well as the evolution of alternative mechanisms for receptor diversification. Such findings blur traditional distinctions between adaptive and innate immunity and emphasize that, throughout evolution, the immune system has used a remarkably extensive variety of solutions to meet fundamentally similar requirements for host protection.

Animals↗
PubMed2004

Crystallization and preliminary X-ray analysis of VCBP3 from Branchiostoma floridae.

VCBPs represent a family of proteins with highly diversified immunoglobulin-like variable regions in species thought to lack an adaptive immune system. These proteins are expected to reveal important structural and functional features that could be highly informative in projecting the evolutionary history of the adaptive immune response. Preliminary X-ray diffraction data from amphioxus (Branchiostoma floridae) VCBP3 crystals were collected to 2.4 A resolution and reduced to primitive trigonal space groups P3(1(2))21. Unit-cell parameters are a = b = 58.99, c = 79.21 A, alpha = beta = 90, gamma = 120 degrees . Two distinct crystallization conditions yielded crystals with similar morphologies and these crystals are isomorphous to each other.

Chitin↗
PubMed2004

Mechanisms of antigen receptor evolution.

The adaptive immune system, which utilizes RAG-mediated recombination to diversify immune receptors, arose in ancestors of the jawed vertebrates approximately 500 million years ago. Homologs of immunoglobulins (Igs), T cell antigen receptors (TCRs), major histocompatibility complex (MHC) I and II, and the recombination activating genes (RAGs) have been identified in all extant classes of jawed vertebrates; however, no definitive ortholog of any of these genes has been identified in jawless vertebrates or invertebrates. Although the identity of the "primoridal" receptor that likely was interrupted by the recombination mechanism in the common ancestor of jawed vertebrates may never be established, many different families of genes that exhibit predicted characteristics of such a receptor have been described both within and outside the jawed vertebrates. Various model systems point toward a range of immune receptor diversity, encompassing many different families of recognition molecules, including non-diversified and diversified Ig-type variable (V) regions, as well as diversified VJ domains, whose functions are integrated in an organism's response to pathogenic invasion. The transition from the primordial antigen receptor to the monomeric Ig-/TCR-like domain and subsequent antigen-specific heterodimer likely involved progressive refinement of unique intermolecular associations in parallel with the acquisition of combinatorial diversity and antigen-specific recognition through somatic modification of the V region. RAG-mediated recombination and associated junctional diversification of both Ig and TCR genes occurs in all jawed vertebrates. In the case of Igs, somatic variation is expanded further through class switching, gene conversion, and somatic hypermutation. Various approaches, including both genomic and protein functional analyses, currently are being applied in jawless vertebrates, protochordates and other invertebrate deuterostome model systems in order to examine both RAG-mediated and alternative forms of antigen receptor diversification. Such studies have uncovered previously unknown mechanisms of generating receptor diversity.

Animals↗
PubMed2004

The phylogenetic origins of the antigen-binding receptors and somatic diversification mechanisms.

The adaptive immune system arose in ancestors of the jawed vertebrates approximately 500 million years ago. Homologs of immunoglobulins (Igs), T-cell antigen receptors (TCRs), major histocompatibility complex I (MHC I) and MHC II, and the recombination-activating genes (RAGs) have been identified in all extant classes of jawed vertebrates; however, no definitive homolog of any of these genes has been identified in jawless vertebrates or invertebrates. RAG-mediated recombination and associated junctional diversification of both Ig and TCR genes occurs in all jawed vertebrates. In the case of Igs, somatic variation is expanded further through class switching, gene conversion, and somatic hypermutation. Although the identity of the 'primordial' receptor that was interrupted by the recombination mechanism in jawed vertebrates may never be established, many different families of genes that exhibit predicted characteristics of such a receptor have been described both within and outside the jawed vertebrates. Recent data from various model systems point toward a continuum of immune receptor diversity, encompassing many different families of recognition molecules whose functions are integrated in an organism's response to pathogenic invasion. Various approaches, including both genomic and protein-functional analyses, currently are being applied in jawless vertebrates, protochordates, and other invertebrate deuterostome systems and may yield definitive evidence regarding the presence or absence of adaptive immune homologs in species lacking adaptive immune systems. Such studies have the potential for uncovering previously unknown mechanisms of generating receptor diversity.

Animals↗
PubMed2002

Identification of diversified genes that contain immunoglobulin-like variable regions in a protochordate.

The evolutionary origin of adaptive immune receptors is not understood below the phylogenetic level of the jawed vertebrates. We describe here a strategy for the selective cloning of cDNAs encoding secreted or transmembrane proteins that uses a bacterial plasmid (Amptrap) with a defective beta-lactamase gene. This method requires knowledge of only a single target motif that corresponds to as few as three amino acids; it was validated with major histocompatibility complex genes from a cartilaginous fish. Using this approach, we identified families of genes encoding secreted proteins with two diversified immunoglobulin-like variable (V) domains and a chitin-binding domain in amphioxus, a protochordate. Thus, multigenic families encoding diversified V regions exist in a species lacking an adaptive immune response.

Amino Acid Sequence↗
PubMed2002

The dual specificity JKAP specifically activates the c-Jun N-terminal kinase pathway.

The involvement of dual specificity phosphatases (DSPs) in the mitogen-activated protein kinase (MAPK) signaling has been mostly limited to the inactivation of MAPKs by the direct dephosphorylation of the TXY motif within their activation loop. We report the cloning and characterization of a murine DSP, called JNK pathway-associated phosphatase (JKAP), which lacks the regulatory region present in most other MAP kinase phosphatases (MKPs) and is preferentially expressed in murine Lin(-)Sca-1(+) stem cells. Overexpression of JKAP in human embryonic kidney 293T cells specifically activated c-Jun N-terminal kinase (JNK) but not p38 and extracellular signal-regulated kinase 2. Overexpression of a mutant JKAP, JKAP-C88S, blocked tumor necrosis factor-alpha-induced JNK activation. Targeted gene disruption in murine embryonic stem cells abolished JNK activation by tumor necrosis factor-alpha and transforming growth factor-beta, but not by ultraviolet-C irradiation, indicating that JKAP is necessary for optimal JNK activation. JKAP associated with JNK and MKK7, but not SEK1, in vivo. However, JKAP did not interact with JNK in vitro, suggesting that JKAP exerts its effect on JNK in an indirect manner. Taken together, these studies identify a positive regulator for the JNK pathway and suggest a novel role for DSP in mitogen-activated protein kinase regulation.

Animals↗