Cell membrane deformation induced by external mechanical stimuli has been studied extensively over the past three decades. The present study focuses on the coupling of in-plane shear H and out-of-plane bending B of liposome membrane and its influences on the deformation of a single vesicle subjected to (i) external compressive load via two parallel platens and (ii) contact forces caused by a rigid substrate. Our results show that the increase of membrane resultant stress in both loading configurations causes the liposome to become more rigid and the degree of vesicle deformation decreases when the in-plane shearing effect is dominant. A theoretical approach is developed to facilitate cell membrane characterization under different biomechanical stimuli.