Bruton's tyrosine kinase

Bruton's tyrosine kinase (abbreviated Btk or BTK) also known as tyrosine-protein kinase BTK is an enzyme that in humans is encoded by the BTK gene. BTK is a kinase that plays a crucial role in B-cell development.

Function

BTK plays a crucial role in B cell maturation as well as mast cell activation through the high-affinity IgE receptor.

Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 binding induces Btk to phosphorylate phospholipase C, which in turn hydrolyzes PIP₂, a phosphatidylinositol, into two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which then go on to modulate the activity of downstream proteins during B-cell signalling.

Clinical significance

Mutations in the BTK gene are implicated in the primary immunodeficiency disease X-linked agammaglobulinemia (Bruton's agammaglobulinemia). Patients with XLA have normal pre-B cell populations in their bone marrow but these cells fail to mature and enter the circulation. The Btk gene is located on the X chromosome. At least 400 mutations of the BTK gene have been identified.

Index of Multiple Deprivation 2000

The Index of Multiple Deprivation 2000 (IMD 2000) showed relative levels of social and economic deprivation across all the counties of England at a ward level, the first national study of its kind.

Deprivation across the 8414 wards in the country was assessed, using the following criteria:

Wards ranking in the most deprived 10 per cent in the country were earmarked for additional funding and assistance.

The five most deprived wards in England were found to be:

The five least deprived wards in England were found to be:

IMD2000 was the subject of some controversy, and was succeeded by the Indices of deprivation 2004 which abandoned ward-level data and sampled much smaller geographical areas.

Wiskott–Aldrich syndrome protein

The Wiskott–Aldrich Syndrome protein (WASp) is a 502-amino acid protein expressed in cells of the hematopoietic system. In the inactive state, WASp exists in an autoinhibited conformation with sequences near its C-terminus binding to a region near its N-terminus. Its activation is dependent upon CDC42 and PIP2 acting to disrupt this interaction, causing the WASp protein to 'open'. This exposes a domain near the WASp C-terminus that binds to and activates the Arp2/3 complex. Activated Arp2/3 nucleates new F-actin. WASp is the founding member of a gene family which also includes the broadly expressed N-WASP (neuronal Wiskott–Aldrich Syndrome protein), and Scar.

Structure and function

The Wiskott–Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton. The presence of a number of different motifs suggests they are regulated by a number of different stimuli, and interact with multiple proteins. These proteins, directly or indirectly, associate with the small GTPase CDC42, known to regulate formation of actin filaments, and the cytoskeletal organising complex, Arp2/3.