reduced o2 tension) and activation of the prostacyclin receptor (ipr). this pathway includes heterotrimeric g proteins, adenylyl cyclase (ac), protein kinase a (pka), cystic fibrosis transmembrane conductance regulator (cftr), and a final conduit that transport atp to vascular lumen (pannexin 1 or voltage-dependent anion channel (vdac)). the released atp acts on purinergic receptors on endothelial cells, triggering the synthesis and release of several vasodilators, like nitric oxide (no) and prostacyclin (pgi2). the current model of leukocyte adhesion cascade includes many steps mentioned in table 1. the integrin-mediated adhesion of leukocytes to endothelial cells is related with morphological changes in both leukocytes and endothelial cells, which together support leukocyte migration through the venular walls. rho and ras small gtpases are involved in the principal leukocyte signaling pathways underlying chemokine-stimulated integrin-dependent adhesion, and have important roles in regulating cell shape, adhesion and motility. the leukocyte adhesion cascade steps and the key molecules involved in each step after a vascular injury occurs, platelets are activated by locally exposed collagen (glycoprotein (gp) vi receptor), locally generated thrombin (par1 and par4 receptors), platelet-derived thromboxane a2 (txa2) (tp receptor) and adp (p2y1 and p2y12 receptors) that is either released from damaged cells or secreted from platelet dense granules. the von willebrand factor (vwf) serves as an essential accessory molecule. in general terms, platelet activation initiated by agonist takes to a signaling cascade that leads to an increase of the cytosolic calcium concentration. consequently, the integrin αiibβ3 is activated and the binding to fibrinogen allows the aggregation of platelets to each other. the increase of cytosolic calcium also leads to shape change and txa2 synthesis, leading to signal amplification. lymphocytes the main goal of biochemical cascades in lymphocytes is the secretion of molecules that can suppress altered cells or eliminate pathogenic agents, through proliferation, differentiation and activation of these cells. therefore, the antigenic receptors play a central role in signal transduction in lymphocytes, because when antigens interact with them lead to a cascade of signal events. these receptors, that recognize the antigen soluble (b cells) or linked to a molecule on antigen presenting cells (t cells), do not have long cytoplasm tails, so they are anchored to signal proteins, which contain a long cytoplasmic tails with a motif that can be phosphorylated (itam – immunoreceptor tyrosine-based activation motif) and resulting in different signal pathways. the antigen receptor and signal protein form a stable complex, named bcr or tcr, in b or t cells, respectively. the family src is essential for signal transduction in these cells, because it is responsible for phosphorylation of itams. therefore, lyn and lck, in lymphocytes b and t, respectively, phosphorylate immunoreceptor tyrosine-based activation motifs after the antigen recognition and the conformational change of the receptor, which leads to the binding of syk/zap-70 kinases to itam and its activation. syk kinase is specific of lymphocytes b and zap-70 is present in t cells. after activation of these enzymes, some adaptor proteins are phosphorylated, like blnk (b cells) and lat (t cells). these proteins after phosphorylation become activated and allow binding of others enzymes that continue the biochemical cascade. one example of a protein that binds to adaptor proteins and become activated is plc that is very important in the lymphocyte signal pathways. plc is responsible for pkc activation, via dag and ca2+, which leads to phosphorylation of carma1 molecule, and formation of cbm complex. this complex activates iκκ kinase, which phosphorylates i-κb, and then allows the translocation of nf-κb to the nucleus and transcription of genes encoding cytokines, for example. others transcriptional factors like nfat and ap1 complex are also important for transcription of cytokines. the differentiation of b cells to plasma cells is also an example of a signal mechanism in lymphocytes, induced by a cytokine receptor. in this case, some interleukins bind to a specific receptor, which leads to activation of mapk/erk pathway. consequently, the blimp1 protein is translated and inhibits pax5, allowing immunoglobulin genes transcription and activation of xbp1 (important for the secretory apparatus formation and enhancing of protein synthesis). also, the coreceptors (cd28/cd19) play an important role because they can improve the antigen/receptor binding and initiate parallel cascade events, like activation o pi3 kinase. pip3 then is responsible for activation of several proteins, like vav (leads to activation of jnk pathway, which consequently leads to activation of c-jun) and btk (can also activate plc). wnt signaling pathway the wnt signaling pathway can be divided in canonical and non-canonical. the canonical signaling involves binding of wnt to frizzled and lrp5 co-receptor, leading to gsk3 phosphorylation and inhibition of β-catenin degradation, resulting in its accumulation and translocation to the nucleus, where it acts as a transcription factor. the non-canonical wnt signaling can be divided in planar cell polarity (pcp) pathway and wnt/calcium pathway. it is characterized by binding of wnt to frizzled and activation of g proteins and to an increase of intracellular levels of calcium through mechanisms involving pkc 50. the wnt signaling pathway plays a significative role in osteoblastogenesis and bone formation, inducing the differentiation of mesenquimal pluripotent cells in osteoblasts and inhibiting the rankl/rank pathway and osteoclastogenesis. rankl/rank signaling pathway rankl is a member of the tnf superfamily of ligands. through binding to the rank receptor it activates various molecules, like nf-kappa b, mapk, nfat and pi3k52. the rankl/rank signaling pathway regulates osteoclastogenesis, as well as, the survival and activation of osteoclasts. adenosine signaling pathway adenosine is very relevant in bone metabolism, as it plays a role in formation and activation of both osteoclasts and osteoblasts. adenosine acts by binding to purinergic receptors and influencing adenylyl cyclase activity and the formation of camp and pka 54. adenosine may have opposite effects on bone metabolism, because while certain purinergic receptors stimulate adenylyl cyclase activity, others have the opposite effect. under certain circumstances adenosine stimulates bone destruction and in other situations it promotes bone formation, depending on the purinergic receptor that is being activated. stem cells self-renewal and differentiation abilities are exceptional properties of stem cells. these cells can be classified by their differentiation capacity, which progressively decrease with development, in totipotents, pluripotents, multipotents and unipotents. self-renewal process is highly regulated from cell cycle and genetic transcription control. there are some signaling pathways, such as lif/jak/stat3 (leukemia inhibitory factor/janus kinase/signal transducer and activator of transcription 3) and bmp/smads/id (bone morphogenetic proteins/ mothers against decapentaplegic/ inhibitor of differentiation), mediated by transcription factors, epigenetic regulators and others components, and they are responsible for self-renewal genes expression and inhibition of differentiation genes expression, respectively. at cell cycle level there is an increase of complexity of the mechanisms in somatic stem cells. however, it is observed a decrease of self-renewal potential with age. these mechanisms are regulated by p16ink4a-cdk4/6-rb and p19arf-p53-p21cip1 signaling pathways. embryonic stem cells have constitutive cyclin e-cdk2 activity, which hyperphosphorylates and inactivates rb. this leads to a short g1 phase of the cell cycle with rapid g1-s transition and little dependence on mitogenic signals or d cyclins for s phase entry. in fetal stem cells, mitogens promote a relatively rapid g1-s transition through cooperative action of cyclin d-cdk4/6 and cyclin e-cdk2 to inactivate rb family proteins. p16ink4a and p19arf expression are inhibited by hmga2-dependent chromatin regulation. many young adult stem cells are quiescent most of the time. in the absence of mitogenic signals, cyclin-cdks and the g1-s transition are suppressed by cell cycle inhibitors including ink4 and cip/kip family proteins. as a result, rb is hypophosphorylated and inhibits e2f, promoting quiescence in g0-phase of the cell cycle. mitogen stimulation mobilizes these cells into cycle by activating cyclin d expression. in old adult stem cells, let-7 microrna expression increases, reducing hmga2 levels and increasing p16ink4a and p19arf levels. this reduces the sensitivity of stem cells to mitogenic signals by inhibiting cyclin-cdk complexes. as a result, either stem cells cannot enter the cell cycle, or cell division slows in many tissues. extrinsic regulation is made by signals from the niche, where stem cells are found, which is able to promote quiescent state and cell cycle activation in somatic stem cells. asymmetric division is characteristic of somatic stem cells, maintaining the reservoir of stem cells in the tissue and production of specialized cells of the same. stem cells show an elevated therapeutic potential, mainly in hemato-oncologic pathologies, such as leukemia and lymphomas. little groups of stem cells were found into tumours, calling cancer stem cells. there are evidences that these cells promote tumor growth and metastasis. oocytes the oocyte is the female cell involved in reproduction. there is a close relationship between the oocyte and the surrounding follicular cells which is crucial to the development of both. gdf9 and bmp15 produced by the oocyte bind to bmpr2 receptors on follicular cells activating smads 2/3, ensuring follicular development. concomitantly, oocyte growth is initiated by binding of kitl to its receptor kit in the oocyte, leading to the activation of pi3k/akt pathway, allowing oocyte survival and development. during embryogenesis, oocytes initiate meiosis and stop in prophase i. this arrest is maintained by elevated levels of camp within the oocyte. it was recently suggested that cgmp cooperates with camp to maintain the cell cycle arrest. during meiotic maturation, the lh peak that precedes ovulation activates mapk pathway leading to gap junction disruption and breakdown of communication between the oocyte and the follicular cells. pde3a is activated and degrades camp, leading to cell cycle progression and oocyte maturation. the lh surge also leads to the production of progesterone and prostaglandins that induce the expression of adamts1 and other proteases, as well as their inhibitors. this will lead to degradation of the follicular wall, but limiting the damage and ensuring that the rupture occurs in the appropriate location, releasing the oocyte into the fallopian tubes. oocyte activation depends on fertilization by sperm. it is initiated with sperm's attraction induced by prostaglandins produced by the oocyte, which will create a gradient that will influence the sperm's direction and velocity. after fusion with the oocyte, plc ζ of the spermatozoa is released into the oocyte leading to an increase in ca2+ levels that will activate camkii which will degrade mpf, leading to the resumption of meiosis. the increased ca2+ levels will induce the exocytosis of cortical granules that degrade zp receptors, used by sperm to penetrate the oocyte, blocking polyspermy. deregulation of these pathways will lead to several diseases like, oocyte maturation failure syndrome which results in infertility. increasing our molecular knowledge of oocyte development mechanisms could improve the outcome of assisted reproduction procedures, facilitating conception. spermatozoon spermatozoon is the male gamete. after ejaculation this cell is not mature, so it can not fertilize the oocyte. to have the ability to fertilize the female gamete, this cell suffers capacitation and acrosome reaction in female reproductive tract. the signaling pathways best described for spermatozoon involve these processes. the camp/pka signaling pathway leads to sperm cells capacitation; however, adenylyl cyclase in sperm cells is different from the somatic cells. adenylyl cyclase in spermatozoon does not recognize g proteins, so it is stimulated by bicarbonate and ca2+ ions. then, it converts adenosine triphosphate into cyclic amp, which activates protein kinase a. pka leads to protein tyrosine phosphorylation. phospholipase c (plc) is involved in acrosome reaction. zp3 is a glycoprotein present in zona pelucida and it interacts with receptors in spermatozoon. so, zp3 can activate g protein coupled receptors and tyrosine kinase receptors, that leads to production of plc. plc cleaves the phospholipid phosphatidylinositol 4,5-bisphosphate (pip2) into diacyl glycerol (dag) and inositol 1,4,5-trisphosphate. ip3 is released as a soluble structure into the cytosol and dag remains bound to the membrane. ip3 binds to ip3 receptors, present in acrosome membrane. in addition, calcium and dag together work to activate protein kinase c, which goes on to phosphorylate other molecules, leading to altered cellular activity. these actions cause an increase in cytosolic concentration of ca2+ that leads to dispersion of actin and consequently promotes plasmatic membrane and outer acrosome membrane fusion. progesterone is a steroid hormone produced in cumulus oophorus. in somatic cells it binds to receptors in nucleus; however, in spermatozoon its receptors are present in plasmatic membrane. this hormone activates akt that leads to activation of other protein kinases, involved in capacitation and acrosome reaction. when ros (reactive oxygen species) are present in high concentration, they can affect the physiology of cells, but when