User:Marcin Jozef Suskiewicz/Sandbox Parvin/

From Proteopedia

Revision as of 14:09, 6 December 2010

Alpha-parvin^[1], also known as actopaxin^[2] or CH domain-containing integrin-linked kinase (ILK)-binding protein (CH-ILK-BP)^[3] is an adapter protein known to interact with a number of focal adhesion proteins leading to focal adhesion stabilisation. Knock-out analysis confirmed it to be essential for efficient directional cell migration during embryogenesis in mice^[4]. Spatially and temporarily regulated dynamic changes in the phosphorylation status of alpha-parvin at serines 4 and 8 and consequent changes in affinities towards its binding partners (icluding CdGAP, TESK1 and possibly others, e.g. ILK) may be responsible for 1) focal adhesion turnover (disassembly of old adhesions, assembly of new ones) and 2) actin cytoskeleton reorganization, two interrelated processes contributing to cell migration.^{[5][6][7][8][9]}

Biological significance

Focal adhesions and cell migration

The extracellular matrix (ECM) composed of matrix molecules such as collagens, laminins, proteoglycans and non-matrix proteins including growth factors, provides physical support and mediates bidirectional flow of signals in all tissues and organs^[10]. Cell-ECM attachments, critical for appropriate localization and functioning of cells, are mediated by integrins.^[11]The engagement of integrins to the ECM results in the recruitment of various proteins to the cell periphery and consequent assembly of dot-like focal complexes (FXs or nascent adhesions), which can mature to much larger, centripetally asymmetrical, focal adhesions (FAs or focal contacts). Focal adhesions are bound to the integrins on one hand and to the actin cytoskeleton on the other, thus accounting for the mechanical continuity and signal transduction between the ECM outside the cell and the cytoskeleton inside the cell.^[12]

The complex FA network (the adhesome), is composed of, among others, actin regulators, Tyr and Ser/Thr kinases and phosphatases, phosphatidylinositols and their modifiers, Rho family GTPases and their effectors. Interactions between these components are mediated by various adapter proteins, including talin, vinculin, paxillin and alpha-parvin^[13].

Alpha-parvin is thus a component of the adhesome, but a more basic unit of which it is part is the IPP (ILK-PINCH-parvin) complex, the central element of which is ILK (integrin-linked kinase). ILK binds both PINCH and alpha-parvin, which do not interact directly with each other, and it is by means of ILK's pseudokinase domain that the complex is recruited to the cytoplasmic tail of integrins. Alpha-parvin is also known to interact with a number of other proteins, including paxillin^[14][15], paxillin's homologue HIC5^[16], TESK1^[17], CdGAP^[18] and alphaPIX^[19].

FAs are dynamic, can grow and shrink and on average, even in stationary cells, gradually disappear tens of minutes after maturation.^[20] The spatially and temporarily regulated FA turnover together with changes in cytoskeletal contractability provide the basis for cell migration in development and regeneration.^[21][22] There is evidence that phosphorylation of alpha-parvin at serines 4 and 8 is correlated with this tightly regulated process. Firstly, phosphorylation of these residues by cyclin B1/cdc2 is observed in the context of mitosis, whereby it contributes to FA disassembly required for cell-rounding prior to cell division, suggesting it may cause a similar effect during cell migration.^[23] Indeed, in migrating cells these residues are observed to be phosphorylated.^[24] What is more, phosphomimetic mutations of serines 4 and 8 to asprtates result in faster migration and spreading, while mutations preventing phosphorylation impair these processes.^[25] Finally, as has already been mentioned in the introduction, studies on knock-out mice suggest alpha-parvin deficiency results in impaired directional migration during embryonic development (heart development in particular).^[26]