Semaphorin signaling. Secreted and membranous semaphorins signal through redundant and alternative pathways. (A) SEMA3-mediated stimulation of plexin-A leads to GSK3-dependent phosphorylation of CRMP and inhibits microtubule assembly by CRMP. Class-3 semaphorins also inhibit Rho-mediated actin polymerization, ERK activation and R-Ras-mediated integrin activation. (B) Upon SEMA4-7 binding, the RasGAP domain of plexin-B/C/D inactivates R-Ras-mediated integrin signaling. This pathway is similarly involved in SEMA3-plexinA signaling. Also, plexin-B/C/D can activate or inhibit RhoA. RhoA regulation sometimes requires the association of the ErbB2 and Met RTK with plexins, which lead to activation of RhoGEF or RhoGAP, respectively. (C) SEMA4-6 reverse signal through their cytoplasmic domain to Abl and EVL to regulate actin dynamics. Gray/black box: R-RasGAP domain. White box: tyrosine kinase domain. Double arrows: proteolytic cleavage. (X) indicates inhibition of the corresponding pathway by SEMA3.

Ephrin signaling. Ephrins signal through reverse signaling and through Eph receptors. (A) reverse signaling occurs through focal adhesion kinase FAK, Abl, the Src family kinase Fyn, Axin and RasGAP. These converge to regulate cell migration through cytoskeleton rearrangement and adhesion. (B) Forward signaling from Eph receptors also engages Abl and RasGAP as well as Rho/Rac to regulate integrin-mediated migration. In addition, Ras downstream signaling controls MAPK and proliferation. Of note, Abl and Fyn signaling are targets of Dasatinib, which specifically inhibits proliferation of lung cancer cells with high expression of Eph receptors. White box: tyrosine kinase domain.

Netrin signaling. The dependence receptor model is described. (A) In absence of netrin binding, DCC and UNC5 are cleaved in their intracellular domain by an active caspase. DCC cleavage leads to the exposure of the addiction dependence domain (ADD) upstream of the caspase cleavage site. This may facilitate the binding of caspase 9 in a complex that involves the adaptor protein APPL (also named DIP13α for DCC-interacting protein 13) to further allow caspase-3 activation. Contrary to ADD exposure in DCC, cleavage of UNC5H releases the death domain from the C-terminal region. This peptide might interact with the death associated protein kinase (DAPK), inducing apoptosis through the activation of caspase-3 and 9. It might also interact with the neurotrophin receptor interacting melanoma-associated antigen (MAGE) homolog NRAGE, inducing apoptosis through either inhibition of the caspase inhibitor XIAP or activation of c-JNK (c-JUN N-terminal kinase). (B) As a consequence of netrin-1 binding, DCC/UNC5 caspase cleavage is blocked. Activation of DCC might release the adaptor APPL, and DCC recruits multiple partners (not represented). Caspase-9 is not activated and mitochondrial-mediated apoptosis is blocked. In addition, DCC might trap caspase-3.22,23,164 UNC5B is a p53 target gene, although binding of netrin-1 inhibits p53-induced apoptosis. Association of netrin-1 to integrins modifies cell adhesion and involves small G proteins for actin reorganization. In addition to apoptosis inhibition, consequences of netrin-1 binding to DCC/UNC5B are regulation of cell motility, invasion and morphogenesis of the vascular system through cytoskeletal rearrangements. Gray box: ADD. Double arrows: proteolytic cleavage. Adapted from reference 22.

Slit signaling. Slit ligand binding to Robo receptors triggers several pathways that control actin reorganization and cell migration. The Rho family of GTPases appears to play a central role in Slit/Robo function. Part of the signaling involves the GAP proteins Vilse and srGAP (SLIT-ROBO Rho GTPase Activating Protein) that inhibit Rac and Cdc42 depending on the cellular context. The repulsive output of Robo1 signaling also involves the binding of Ena, an actin bundling protein which can be antagonized by Abl binding and phosphorylation. The protein Mena is involved in Robo4-mediated repulsion. Gray/black box: cytoplasmic conserved motifs (CC0-3).

Notch signaling. Notch is presented to its ligand as a heterodimer resulting from processing by a furin-like protease during transit to the plasma membrane.165 Ligand binding triggers intra-membrane regulated cleavage of Notch within the juxtamembrane and transmembrane domains, ultimately leading to the release of the Notch intracellular domain (NICD). NICD then translocates to the nucleus where it directly interacts with the CSL (CBF1, Su(H), LAG1) transcription factor. The transcriptional repressor CoR is released. Recruitment of co-activators, including Mastermind, turns on expression of Notch target genes. These targets include a set of transcriptional repressors (Hes1, Hes5, Hey1, Hey2 and HeyL) of the basic helix-loop-helix (bHLH) family that repress expression of other bHLH genes involved in cell differentiation like the ubiquituous E2A factors and Mash1 (mammalian achaete-scute homolog-1), MyoD and others. The ultimate consequence is the regulation of cell fate and differentiation status. Gray box: NICD.

Lung development. Human lung development is organized in five distinct periods.166 The first embryonic period (weeks 3–7) leads to the formation of two lung buds at the ventral-lateral aspect of the foregut, followed by the formation of the major bronchi and division of tracheal-esophageal tube. During the second pseudoglandular period (weeks 5–17), bronchial branches, acinar tubules and buds proliferate, and vasculogenesis and innervation occur. Later (weeks 16–26), in the canalicular period, pulmonary vascular bed and acinus organize and innervation increases. Then, the saccular period (weeks 24–38) is characterized by dilation of peripheral airspaces, differentiation of the respiratory epithelium, an increased vascularity of the saccules and surfactant synthesis. Finally, growth and septation of alveoli, and maturation of the pulmonary vascular system take place from week 38 to maturity (alveolar period).