Regulated expression of focal adhesion kinase-related nonkinase, the autonomously expressed C-terminal domain of focal adhesion kinase

Focal adhesion kinase (FAK) has been implicated in cellular processes that control cell adhesion, migration, cell cycle progression, and apoptosis. FR NK (FAK-related nonkinase) is the autonomously expressed, noncatalytic C-te rminal portion of FAK. When ectopically expressed in cells, FRNK has been s hown to act as a negative regulator of FAK activity, inhibiting cell spread ing, migration, and cell cycle progression. The mechanisms that regulate FR NK expression during embryonic development and the functional role of FRNK in normal cell homeostasis remain poorly understood. Herein we show that FR NK expression in chicken cells is directed by an alternative promoter resid ing within an intron of FAK positioned 3' of the exon encoding sequences fo r the catalytic domain and 5' of the exon encoding sequences for the C-term inal domain of FAK (e.g., FRNK). Using probes specific for FRNK, we show th at FRNK expression occurs early in chicken embryogenesis, being readily det ected at day 3, 6, or 9. Late in embryogenesis, at day 18, FRNK is expresse d in a tissue-specific manner, predominately in lung and intestine cells. W estern blot analysis of mouse tissues with a FAK-specific antibody revealed the expression of FRNK in the mouse lung. Reverse transcriptase PCR analys is of mouse lung RNA revealed the presence of spliced FRNK mRNAs containing 5' untranslated sequences derived from a positionally conserved exon prese nt in the mouse genome. FAK is the first example of a tyrosine kinase regul ated by a domain under the control of an alternative intronic promoter. It is also the first example of a focal adhesion-associated protein regulated by such a mechanism and thus represents a novel means for the modulation of cell adhesion signaling.