Cell adhesion signals regulate proliferation through cyclins D and E. Numerous extracellular cues mediated through transmembrane or membrane-proximal proteins regulate cyclin D and E, controlling progression through G₁. Activation of integrin pathways predominantly promotes proliferation, while merlin- and cadherin-dependent signaling predominantly limits proliferation.

Different classes of extracellular cue regulate spindle orientation. Signals from a neighboring hub cell (via junctional complexes, [50 •• ]), planar cell polarity signaling complexes [48], from extracellular matrix (ECM) [45 • ], and potentially from directional flow of fluids (sensed by cilia, [49 •• ]) regulates spindle orientation. Adhesion and polarity complexes on the surface of the guided cell sense these cues and transmit them to the mitotic machinery. In some examples, discrete pools of APC at the cell cortex and at the centrosome anchor extended bridges of signaling and cytoskeletal proteins that orient the mitotic spindle [44].

Interdependence of cell polarity and cell cycle pathways. Interaction map of highly connected protein classes (predicted by gene ontology) from a high throughput yeast two-hybrid based analysis of the yeast proteome, modified from [1]. Cell polarity proteins provide an important hub connecting cell architecture, signal transduction and cell cycle progression.

Reciprocal regulation of mitotic and adhesion signaling. (a) At G₂/M transition, disassembly of focal adhesion complexes (blue) is accompanied by phosphorylation of FAK, HEF1, Pak, paxillin, actopaxin, Src and others by mitotic kinases (green represents phosphorylated/inactive for attachment signaling). Src activation at mitotic entry may disrupt adhesion through phosphorylation of the transmembrane glycoprotein TRASK. (b) During early mitosis, centrosomal HEF1, Pak, and Ajuba activate Aurora A, which activates Cdk1/cyclin B. A Zyxin-Lats complex is also targeted to the mitotic spindle, to regulate Cdk1/cyclinB. Additional interactions — including activation of RhoA by Hef1 and ECT2, Par complex association with ECT2, and Aurora A interaction with the RhoA effector p160ROCK — are indicated. (c) Cell attachment through integrins is required for abscission at cytokinesis. Action of the exocyst complex and SNARE complexes delivers components such as Src to the cleavage furrow to promote abscission. Basal relocalization of proteins such as HEF1, TRASK and Pak may contribute to re-establishment of focal contacts, while RhoA activity contributes to multiple events in cytokinesis (29]. In some systems for asymmetric cell division, abscission cues are provided from only one of the two prospective daughter cells, and may involve transient movement of the centrosome to the midbody.