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Cell polarity, which consists of the morphological, structural, and functional organization of cells along a defined axis, is a feature of healthy cells and tissues. In contrast, abnormal polarity is a hallmark of cancer cells. At the molecular level, key evolutionarily conserved proteins that control polarity establishment and maintenance in various contexts are frequently altered in cancer, but the relevance of these molecular alterations in the oncogenic processes is not always clear. Here, we summarize the recent findings, shedding new light on the involvement of polarity players in cancer development, and discuss the possibility of harnessing cell polarity changes to better predict, diagnose, and cure cancers., (© 2023 Peglion and Etienne-Manneville.)

Migration is a key cellular process, involved during morphogenetic movements as well as in the adult where it participates in immune cell trafficking, wound healing or tumour invasion. As they migrate, cells interact with a microenvironment composed of extracellular matrix and neighbouring cells. Cell-cell adhesions ensure tissue integrity while they allow migration of single or grouped cells within this tissue. Cadherin and nectin-based adherens junctions are key players in intercellular interactions. They are used as adhesive complexes whose mechanical properties improve cell coordination during collective migration and promote cell motility on cadherin substrates. In addition, adherens junctions transduce signals that actively participate in the control of directed cell migration, by providing polarity cues and also participating in contact inhibition of motility.

Microtubules are highly dynamic structures whose regulation is crucial for cell division, cell polarity, cell migration, or neuronal differentiation. Because they contribute to most cellular functions, they must be regulated in response to extracellular and intracellular signals. The parameters of microtubule dynamics are numerous and complex and the connection between signaling pathways and regulation of microtubule dynamics remain obscure. Recent observations reveal key players that can both integrate the diversity of signaling cascades and directly influence microtubule dynamics. I review here how modifications of the tubulin dimer, tubulin modifying enzymes, and microtubule-associated proteins are directly involved in the regulation of microtubule behavior and functions., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Although proteins involved in determining apical-basal cell polarity have been directly linked to tumorigenesis, their precise roles in this process remain unclear. A recent report in BMC Biology clarifies the signaling pathways that control cell polarity, proliferation and apoptosis downstream of the tumor suppressor and apical-basal polarity determinant Scribble.

Glial cells, which include myelinating oligodendrocytes, Schwann cells and astrocytes, fulfil a large variety of functions that are critical for the development, functioning and regeneration of neurons. Some of these glial functions have been shown to require polarization of the intracellular machinery. Although the initial signals leading to glial cell polarization during development and in the adult are not completely elucidated, crucial molecules such as proteins of the extracellular matrix and their membrane receptors have been identified. A general picture of the intracellular signalling pathways controlling polarity in glial cells is also emerging and shows that highly conserved and ubiquitously expressed polarity proteins are involved.

Rho GTPases are molecular switches that control a wide variety of signal transduction pathways in all eukaryotic cells. They are known principally for their pivotal role in regulating the actin cytoskeleton, but their ability to influence cell polarity, microtubule dynamics, membrane transport pathways and transcription factor activity is probably just as significant. Underlying this biological complexity is a simple biochemical idea, namely that by switching on a single GTPase, several distinct signalling pathways can be coordinately activated. With spatial and temporal activation of multiple switches factored in, it is not surprising to find Rho GTPases having such a prominent role in eukaryotic cell biology.

We describe here a signal transduction pathway controlling the establishment of mammalian cell polarity. Scratching a confluent monolayer of primary rat astrocytes leads to polarization of cells at the leading edge. The microtubule organizing center, the microtubule cytoskeleton, and the Golgi reorganize to face the new free space, and directed cell protrusion and migration specifically occur perpendicularly to the scratch. We show here that the interaction of integrins with extracellular matrix at the newly formed cell front leads to the activation and polarized recruitment of Cdc42, which in turn recruits and activates a cytoplasmic mPar6/PKCzeta complex. Localized PKCzeta activity, acting through the microtubule motor protein dynein, is required for all aspects of induced polarity in these cells.

In the CNS, astrocytes play a key role in immunological and inflammatory responses through ICAM-1 expression, cytokine secretion (including TNF-alpha), and regulation of blood-brain barrier permeability. Because ICAM-1 transduces intracellular signals in lymphocytes and endothelial cells, we investigated in the present study ICAM-1-coupled signaling pathways in astrocytes. Using rat astrocytes in culture, we report that ICAM-1 binding by specific Abs induces TNF-alpha secretion together with phosphorylation of the transcription factor cAMP response element-binding protein. We show that ICAM-1 binding induces cAMP accumulation and activation of the mitogen-activated protein kinase extracellular signal-regulated kinase. Both pathways are responsible for cAMP response element-binding protein phosphorylation and TNF-alpha secretion. Moreover, these responses are partially dependent protein kinase C, which acts indirectly, as a common activator of cAMP/protein kinase A and extracellular signal-regulated kinase pathways. These results constitute the first evidence of ICAM-1 coupling to intracellular signaling pathways in glial cells and demonstrate the convergence of these pathways onto transcription factor regulation and TNF-alpha secretion. They strongly suggest that ICAM-1-dependent cellular adhesion to astrocytes could contribute to the inflammatory processes observed during leukocyte infiltration in the CNS.