Inositol phospholipids play multiple roles in cell signalling systems. Two widespread eukaryotic phosphoinositide-based signal transduction mechanisms, phosphoinositidase C-catalysed phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) hydrolysis and 3-OH kinase-catalysed PtdIns(4,5)P2 phosphorylation, make the second messengers inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) sn-1,2-diacylglycerol and PtdIns(3,4,5)P3. In addition, PtdIns(4,5)P2 and PtdIns3P have been implicated in exocytosis and membrane trafficking. We now show that when the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe are hyperosmotically stressed, they rapidly synthesize phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2) by a process that involves activation of a PtdIns3P 5-OH kinase. This PtdIns(3,5)P2 accumulation only occurs in yeasts that have an active vps34-encoded PtdIns 3-OH kinase, showing that this latter kinase makes the PtdIns3P needed for PtdIns(3,5)P2 synthesis and indicating that PtdIns(3,5)P2 may have a role in sorting vesicular proteins. PtdIns(3,5)P2 is also present in mammalian and plant cells: in monkey Cos-7 cells, its labelling is inversely related to the external osmotic pressure. The stimulation of a PtdIns3P 5-OH kinase-catalysed synthesis of PtdIns(3,5)P2, a molecule that might be a new type of phosphoinositide 'second messenger, thus appears to be central to a widespread and previously uncharacterized regulatory pathway.
The myeloid restricted membrane glycoprotein, CD33, is a member of the recently characterized "sialic acidbinding immunoglobulin-related lectin" family. Although CD33 can mediate sialic acid-dependent cell interactions as a recombinant protein, its function in myeloid cells has yet to be determined. Since CD33 contains two potential immunoreceptor tyrosine-based inhibition motifs in its cytoplasmic tail, we investigated whether it might act as a signaling receptor in myeloid cells. Tyrosine phosphorylation of CD33 in myeloid cell lines was stimulated by cell surface cross-linking or by pervanadate, and inhibited by PP2, a specific inhibitor of Src family tyrosine kinases. Phosphorylated CD33 recruited both the protein-tyrosine phosphatases, SHP-1 and SHP-2. CD33 was dephosphorylated in vitro by the co-immunoprecipitated tyrosine phosphatases, suggesting that it might also be an in vivo substrate. The first CD33 phosphotyrosine motif is dominant in CD33-SHP-1/SHP-2 interactions, since mutating tyrosine 340 in a CD33-cytoplasmic tail fusion protein significantly reduced binding to SHP-1 and SHP-2 in THP-1 lysates, while mutation of tyrosine 358 had no effect. Furthermore, the NH 2 -terminal Src homology 2 domain of SHP-1 and SHP-2, believed to be essential for phosphatase activation, selectively bound a CD33 phosphopeptide containing tyrosine 340 but not one containing tyrosine 358. Finally, mutation of tyrosine 340 increased red blood cell binding by CD33 expressed in COS cells. Hence, CD33 signaling through selective recruitment of SHP-1/ SHP-2 may modulate its ligand(s) binding activity.Over the last few years, a novel family of sialic acid-dependent recognition molecules has emerged. This family, recently designated "siglecs" (sialic acid-binding Ig-related lectins), is a structurally related subgroup of the immunoglobulin superfamily that includes CD22 (siglec-2), sialoadhesin (siglec-1), MAG (siglec-4), CD33 (siglec-3), and the newest member of the family, siglec-5 (1). All siglecs have an NH 2 -terminal V-set Ig-like domain that contains the sialic acid binding site, followed by varying numbers of C2-set domains. In addition to common structural features that would appear to adapt these molecules for functional protein-carbohydrate cellular interactions, each member exhibits a very specific pattern of tissue distribution. While CD22 is restricted to B cells, sialoadhesin to macrophages, and myelin-associated glycoprotein (MAG) to myelinating oligodendrocytes and Schwann cells, CD33 and siglec 5 are expressed only on cells of the myelomonocytic lineage.CD22 is perhaps the best characterized member of the siglec family. In addition to being an adhesion receptor for sialic-acid bearing ligands on leukocytes and erythrocytes, CD22 has an important regulatory role as a signal transduction molecule in B cells (2, 3). The cytoplasmic tail of CD22 has six tyrosines, two of which are encompassed within sequences which conform with immunoreceptor tyrosine-based activation motifs (ITAM), 1 while the other four form po...
Platelets are highly reactive cell fragments that adhere to exposed extracellular matrix (ECM) and prevent excessive blood loss by forming clots. Paradoxically, megakaryocytes, which produce platelets in the bone marrow, remain relatively refractory to the ECM-rich environment of the bone marrow despite having the same repertoire of receptors as platelets. These include the ITAM (immunoreceptor tyrosine-based activation motif)-containing collagen receptor complex, which consists of glycoprotein VI (GPVI) and the Fc receptor γ-chain, and the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing receptor G6b-B. We showed that mice lacking G6b-B exhibited macrothrombocytopenia (reduced platelet numbers and the presence of enlarged platelets) and a susceptibility to bleeding as a result of aberrant platelet production and function. Platelet numbers were markedly reduced in G6b-B-deficient mice compared to those in wild-type mice because of increased platelet turnover. Furthermore, megakaryocytes in G6b-B-deficient mice showed enhanced metalloproteinase production, which led to increased shedding of cell-surface receptors, including GPVI and GPIbα. In addition, G6b-B-deficient megakaryocytes exhibited reduced integrin-mediated functions and defective formation of proplatelets, the long filamentous projections from which platelets bud off. Together, these findings establish G6b-B as a major inhibitory receptor regulating megakaryocyte activation, function, and platelet production.
During Pleistocene, the Laurentide ice sheet rearranged and diversified biotic distributions in eastern North America, yet had minimal physical impact in western North America where lineage diversification is instead hypothesized to result from climatic changes. If Pleistocene climatic fluctuations impacted desert species, the latter would reflect patterns of restricted gene flow concomitant with indications of demographic bottlenecks. Accordingly, molecular evidence for refugia should be present within these distributions and for subsequent range expansions as conditions improved. We sought answers to these questions by evaluating mitochondrial DNA (mtDNA) sequences from four species of rattlesnakes [Crotalus mitchellii (speckled rattlesnake), Crotalus cerastes (sidewinder), Crotalus tigris (tiger rattlesnake), Crotalus ruber (red diamond rattlesnake)] with distributions restricted to desert regions of southwestern North America. We inferred relationships using parsimony and maximum likelihood, tested intraspecific clades for population expansions, applied an isolation-with-migration model to determine bi-directional migration rates (m) among regions, and inferred divergence times for species and clades by applying a semiparametric penalized likelihood approach to our molecular data. Evidence for significant range expansion was present in two of eight regions in two species (Crotalus mitchellii pyrrhus, C. tigris region north). Two species (C. cerastes, C. mitchellii) showed a distribution concomitant with northward displacement of Baja California from mainland México, followed by vicariant separation into subclades. Effects of Pleistocene climate fluctuations were found in the distributions of all four species. Three regional diversification patterns were identified: (i) shallow genetic diversity that resulted from Pleistocene climatic events (C. tigris, C. ruber); (ii) deep Pleistocene divisions indicating allopatric segregation of subclades within refugia (C. mitchellii, C. cerastes); and (iii) lineage diversifications that extended to Pliocene or Late Miocene (C. mitchellii, C. cerastes). Clade-diversifying and clade-constraining effects impacted the four species of rattlesnakes unequally. We found relatively high levels of molecular diversification in the two most broadly distributed species (C. mitchellii, C. cerastes), and lower levels of genetic diversification in the two species (C. tigris, C. ruber) whose ranges are relatively more restricted. Furthermore, in several cases, the distributions of subspecies were not congruent with our molecular information. We suggest regional conservation perspectives for southwestern deserts cannot rely upon subspecies as biodiversity surrogates, but must instead employ a molecular and deep historical perspective as a primary mechanism to frame biodiversity reserves within this region.
Genetic diversity in remnant populations of the Sonoran topminnow Poeciliopsis occidentalis (Pisces: Poeciliidae) from Arizona, where the species is endangered, is compared with that in populations from Sonora, Mexico, where the fish is widespread and abundant. Geographically peripheral Arizona populations contain substantially lower levels of genetic variation than do Mexican populations near the center of the species' range. Allelic differences among three genetically and geographically distinct groups are responsible for 53 percent of the total genetic diversity in this species, 26 percent is due to differences among local populations within the groups, and 21 percent is due to heterozygosity within local populations. Recommendations for conservation and restocking efforts in Arizona are based on these genetic findings.
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